In Brief

Diabetes during pregnancy is a major risk factor for poor fetal, neonatal, and maternal outcomes; however, the risk can be greatly reduced by early institution of medical nutritional therapy and treatment. Maintaining maternal glycemia as near to normal as possible reduces the risk of congenital anomalies, macrosomia, neonatal , and large-for-gestational-age infants. Achieving normoglycemia has usually been accomplished with human insulin. However, the newer rapid-acting insulin analogs lispro and aspart, when com- pared to regular human insulin, demonstrate both efficacy and safety for the treatment of diabetes during pregnancy. NPH insulin is the only basal insulin that has been studied in pregnancy. There are not yet any published controlled studies evaluating the long-acting insulin analogs for use in pregnancy.

Insulin Analogs and Pregnancy

Pregnancy complicated by diabetes nancy can also decrease the preva- occurs in ~ 4% of pregnancies in the lence of neonatal hypoglycemia, United States.1 With appropriate insti- macrosomia, intrauterine death, and Angelina L. Trujillo, MD, FACE tution of intensive diabetes therapy and cesarean delivery.5–7 Achieving near- maintenance of glucose levels to normal glycemia means normalizing

achieve a lowering of hemoglobin A1c not only fasting glucose, but also (A1C) levels before and during preg- postprandial hyperglycemia to reduce nancy complicated by diabetes, the rate the risk of an adverse pregnancy out- of fetal and maternal complications come.8–10 The infant mortality rate is can be reduced to the rate observed nearly zero when blood glucose con- among nondiabetic pregnancies.2 centration is maintained at near-nor- Whether the pregnancy is classified as moglycemia.11 In both type 1 and type pregestational diabetes (occurring in 2 diabetes, controlling pre- and post- women who have been diagnosed with prandial hyperglycemia can best be type 1 or type 2 diabetes before preg- accomplished during pregnancy by nancy) or as gestational diabetes melli- administering insulin via continuous tus (GDM, occurring when a nondia- subcutaneous insulin infusion from an betic woman develops diabetes only insulin pump or by self-administration during pregnancy), the goal of treat- of multiple daily injections of an inter- ment is to maintain maternal glucose mediate-acting basal human insulin levels as near to normal as possible (neutral protamine Hagedorn [NPH] throughout the pregnancy. insulin) combined with a short-acting Pregestational diabetes is a major or rapid-acting insulin. In GDM, risk factor for spontaneous abortions achieving normoglycemia can initially and congenital malformations, but the be attempted with medical nutrition risk can be significantly reduced when therapy and lifestyle modifications, hyperglycemia is controlled before but frequently, NPH insulin combined conception and during the early first with a short-acting or rapid-acting trimester when fetal organogenesis insulin must be added to attain opti- occurs.3,4 In both pregestational dia- mal glucose levels. betes and GDM, achieving near-nor- Throughout pregnancy, the placenta mal glycemic levels throughout preg- not only produces hormones that alter 94 Diabetes Spectrum Volume 20, Number 2, 2007 linemia can also produce neonatal Fr

hypoglycemia after the infant is deliv- Pregnancy and Diabetes / om Research Practice to ered and is no longer exposed to maternal hyperglycemia. Treatment of diabetic pregnant women with insulin to maintain maternal glucose levels near normal will prevent the develop- ment of fetal hyperinsulinemia in utero and decrease the risk of adverse fetal or neonatal outcomes associated with excess fetal growth. The insulin requirement necessary to achieve near-normal maternal glycemia is based on the patient’s weight and the number of weeks of gestation (Table 1).18 In recent years, molecularly engi- neered insulin analogs (the “new” ) have been developed and become available for the treatment Figure 1. Development of fetal hyperinsulinemia. Adapted from Ref. 15. of patients with hyperglycemia and diabetes. The currently available rapid-act- ing insulin analogs are lispro, aspart, Table 1. Calculation of Insulin Dosing and glulisine; the long-acting insulin analogs are glargine and detemir. Lispro, aspart, and glulisine are simi- • Woman’s weight in pounds ÷ 2.2 = woman’s weight in kilograms lar rapid-acting formulations used pri- • Weight in kilograms × k = total insulin requirement marily for mealtime insulin require- ments, whereas glargine and detemir → k = 0.7, 0.8, and 0.9 for first, second, and third trimesters, respectively are long-acting basal formulations.19–21 • 50% of total insulin requirement = daily basal insulin dosage provided by Also available are two biphasic for- mulations: biphasic aspart, which is a long-acting insulin mixture of 30% aspart with 70% pro- → A M Administered before breakfast (8:00 . .), before supper taminated aspart, and biphasic lispro (4:00 P.M.), and at midnight either consisting of 25% lispro and • 50% of total insulin requirement = daily bolus insulin dosage provided by 75% protaminated lispro or 50% rapid-acting and 50% protaminated lispro. The insulin analogs are produced → Administered before breakfast (8:00 A.M.), before lunch (noon), by recombinant DNA methods. and before supper (4:00 P.M.) Lispro, prepared by E. coli, differs Adapted from Ref. 18. from human insulin by two amino acid substitutions on the insulin β- chain; a lysine is substituted at posi- maternal carbohydrate and lipid Because of the facilitated diffusion tion 28 and a proline at position 29, metabolism, but it also controls the of glucose across the placenta, the both of which are the reverse of transplacental passage of glucose, fat, maternal glucose level determines the human insulin. Aspart uses saccha- and protein to provide fuel energy and glucose level of the fetus. When the romyces cerevisiae (yeast) to replace nutrients to the developing fetus. maternal glucose level is high, the the proline at position 28 with an Maternal insulin is not transferred fetus becomes hyperglycemic, result- aspartic acid. Glulisine also has a dou- across the placenta unless the insulin is ing in stimulation of the fetal pancreas ble substitution, replacing asparagine 12,13 bound to IgG antibodies. A study by to produce high levels of insulin with lysine at position 3 and lysine 14 15 Balsells et al. evaluated 50 women (Figure 1). with glutamic acid at position 29. with GDM before and after treatment Because insulin is a growth factor, These modifications of the insulin β- with human insulin, which is immuno- the high fetal insulin level increases chain inhibit the self-aggregation of genic, and found that 44% developed intrauterine fetal growth, producing a insulin to form dimers and hexamers, insulin antibodies. They also found newborn that is large for gestational resulting in monomers that are rapidly that cord blood titers at delivery age (LGA; weight > 90th percentile) or absorbed when administered subcuta- 16 reflected the maternal antibody levels, has macrosomia (weight > 4,000 g). neously and thus allowing a faster indicating transplacental passage of Both conditions are frequently associ- onset of action. human insulin when bound with ated with birth trauma, especially Glargine was the first long-acting maternal antibodies. In the same study, shoulder dystocia, which occurs in analog to become commercially avail- the status of the maternal insulin anti- 0.6–1.4% of fetuses weighing able. It has a glycine substituted for body did not appear to have an impact 2,500–4,000 g and in 5–9% of fetuses asparagine at position 21 on the 17 on fetal outcome. weighing > 4,000 g. Fetal hyperinsu- insulin α-chain and two arginines 95 Diabetes Spectrum Volume 20, Number 2, 2007 within 10–15 minutes, reaches peak Table 2. Insulin and Insulin Analogs concentration within 30–60 minutes and has a duration of action up to 3–4 hours.20 Aspart is similar to lispro Insulin Onset of action Time to peak Maximum but may have a slightly longer time to (minutes) concentration duration of peak concentration (40–50 minutes) (minutes) action (hours) as well as a slightly longer duration of 22 30–60 90–120 5–12 action (3–5 hours). Glulisine also has a similar onset and duration of action, Insulin lispro 10–15 30–60 3–4 but has a slightly longer time to reach (Humalog) peak concentration (55 minutes).23 Overall, when administered subcuta- 10–15 40–50 3–5 neously, the rapid-acting insulin 10–15 55 3–5 analogs appear to have very similar pharmacodynamic and pharmacoki- NPH insulin 60–120 240–480 10–20 netic profiles.24–26 Compared with regu- lar human insulin, which has an onset 60–120 None 24 of action of 30–45 minutes and a rela- 60–120 None 20 tively prolonged effect of 2–3 hours, the rapid-acting insulin analogs have Adapted from Refs. 19 and 20. each demonstrated faster onset of action, earlier peak concentration, and briefer duration of action to Table 3. Current Categories for Drug Use in Pregnancy achieve a more physiological dosing as Assigned by the U.S. Food and Drug Administration of insulin for lowering of prandial hyperglycemia while avoiding late- 27 Category Description onset hypoglycemia. A No increased risk of fetal abnormalities have been demonstrated in Long-Acting Insulin Analogs adequate, well-controlled studies in pregnant women. Glargine has a longer time to onset of action (1.5 hours) compared to NPH B There are no adequate and well-controlled studies in pregnant women; (0.8 hour) and ultralente insulin (1 however, animal studies have not revealed evidence of harm to the fetus. hour), whereas the duration of action C There are no adequate and well-controlled studies in pregnant women; of glargine is longer (20.5 hours) than however, an adverse effect has been shown in animal studies. that of NPH (13.2 hours) and is simi- -or- lar to that of ultralente (19 hours) 28 Adequate and well-controlled studies in pregnant women have failed to (Table 2). Ultralente insulin is no show a risk to the fetus; however, an adverse effect has been shown in longer available. In addition, several animal studies. studies have reported less nocturnal hypoglycemia in both type 1 and type D A risk to the fetus has been demonstrated in adequate, well-controlled or 2 diabetes, and in type 2 diabetes, observational studies in pregnant women; however, the benefits of thera- there has been less weight gain with py may outweigh the potential risk. glargine than with NPH.29–31 Detemir appears to have a similar X Positive evidence of fetal abnormalities has been demonstrated in profile to glargine, with slow absorption adequate well-controlled or observational studies in pregnant women or of 3–4 hours and a prolonged effect up in animals. Therefore, the use of the product is contraindicated in to 24 hours32,33(Table 2); however, the women who are or may become pregnant. best profiles are achieved when the Adapted from Ref. 36. insulin is administered twice daily. In clinical studies, detemir also demon- strated lower risk of nocturnal hypo- added to the carboxyl terminal of the albumin binding that prolongs glycemia and less weight gain compared β-chain at positions 31 and 32. These absorption to reach a maximum con- to NPH in type 1 diabetes.33–35 amino acid modifications shift the iso- centration in 6–8 hours and prolongs The long-acting insulin analogs, electric point of the insulin molecule the duration of action up to 24 hours. when used in nonpregnant patients from a pH of 5.4 toward a neutral with diabetes, appear to be most use- pH, which delays its absorption and Rapid-Acting Insulin Analogs ful as basal insulin because of their prolongs the duration of action. Compared with regular insulin, the long duration and lack of a peak. Detemir is produced by the elimi- rapid-acting insulin analogs have a more nation of threonine at position 30 and rapid onset of action as well as a more Efficacy and Safety of Insulin Analogs the addition of myristic acid, a 14-car- rapid decline in concentration, which is During Pregnancy bon fatty acid chain, to the lysine advantageous for reducing postprandial All of the insulin analogs have been located at position 29 of the β-chain. hyperglycemia while avoiding late assigned a “safety during pregnancy” This acylation results in increased self- hypoglycemic events (Table 2). risk factor by the U.S. Food and Drug aggregation and greater reversible Lispro, with an onset of action Administration (Table 3).36 Lispro and 96 Diabetes Spectrum Volume 20, Number 2, 2007 aspart are the only insulin analogs There have been no comparator- among insulin-treated patients with Fr 49,50 currently classified as pregnancy risk controlled studies using the long-act- type 1 diabetes. Because lispro binds Pregnancy and Diabetes / om Research Practice to Category B, which is the same risk ing insulin analogs during pregnancy; more than insulin to the IGF-1 recep- category as regular insulin. however, there have been several case tor, it was postulated in an initial The benefit of controlling maternal reports in which glargine was used for report in 1999 that if a patient were glycemia during pregnancy by reduc- the treatment of hyperglycemia during treated with lispro during pregnancy, ing hyperglycemia and avoiding hypo- pregnancy. These reports suggest that, there was a potential risk for increasing glycemia has been well document- compared to NPH, glargine results in the development of diabetic retinopa- ed.2,3,37 Until the introduction of the improved glycemic control without thy.49 The authors had reported on insulin analogs, glycemic control dur- any nocturnal hypoglycemia.46–48 three pregnant women treated with ing pregnancy was usually managed Although the insulin analogs appear lispro who progressed from no back- with diet and human insulin. to be effective and efficacious for con- ground retinopathy to bilateral prolif- Lispro has been the most well stud- trolling maternal hyperglycemia, there erative diabetic retinopathy.51 Howev- ied during pregnancy. In pregnant have been several concerns regarding er, subsequent case reports comparing women with type 1 diabetes, lispro has their safety during pregnancy. lispro to regular insulin have clearly been shown to reduce A1C levels and shown that the incidence for progres- postprandial glucose levels to lower or Safety of Insulin Analogs sion of retinopathy is no different with similar levels as those achieved with Retinopathy and analogs. During the lispro than with regular insulin.52,53 regular insulin but with fewer severe early weeks of pregnancy, women with Table 4 summarizes the results of stud- hypoglycemic events than with regular the greatest decrease in A1C have an ies evaluating retinopathy compared to insulin.38–43 Similar findings have been increased risk for progression of regular insulin in pregnant women reported for aspart in the treatment of retinopathy. Reports early in the clini- with type 1 diabetes, type 2 diabetes, GDM when compared to regular cal use of lispro proposed that this or GDM. insulin.44,45 From these data, lispro and had a potential risk for Congenital anomalies and analogs. aspart appear to be as efficacious as developing or exacerbating diabetic The increased potential for congenital regular insulin for improving glucose retinopathy during pregnancy. These malformations resulting from lispro control while avoiding late hypo- reports were based on the greater has also been considered. However, glycemic events during management of homology of lispro with insulin-like when outcomes of lispro treatment pregnancy complicated by diabetes. At growth factor 1 (IGF-1), a growth hor- during pregnancy were compared to present, there are no studies evaluating mone that has been indirectly implicat- those of pregnant women treated with the use of glulisine during pregnancy. ed in the development of retinopathy regular insulin, there was no increased

Table 4. Retinopathy and Rapid-Acting Insulin Analogs in Pregnancy

Studies n Type of diabetes Insulin Outcome Lispro Aspart Regular Human Animal

Kitzmiller et al.51 14 Type 1 and 2 14 3 progressed from no background DR to bilateral PDR including 2 vitreous hemorrhages

Bhattacharyya 40 27 with type 1 16 21 3 No progression of retinopathy et al.52 and 3 with type 2 from baseline

Buchbinder et al.53 54 Type 1 12 42 No progression in the lispro group; 6 progressed in the regular insulin group

Persson et al.41 33 Type 1 16 0 17 No difference in progression of DR in both groups; lispro = 3/16; regular = 6/17 with 1 PDR

Masson et al.42 76 Type 1 76 0 0 None without DR at baseline progressed to DR; 6 with DR at base- line required laser therapy for PDR

Loukovaara et al.43 72 Type 1 37 35 2 lispro patients developed bilateral PDR during pregnancy; 2 regular insulin patients developed PDR postpartum

Jovanovic et al.38 42 GDM 19 0 23 No differences in maternal, fetal, or neonatal outcomes DR, diabetic retinopathy; PDR, proliferative diabetes retinopathy.

97 Diabetes Spectrum Volume 20, Number 2, 2007 Table 5. Congenital Anomalies Among Pregnancies Treated With Rapid-Acting Insulin Analogs

Studies n Type of diabetes Diet Insulin Outcome Lispro Regular human

Bhattacharyya 619 81 had type 1 or 323 101 195 Diet-treated 5.2% had Down’s, hydronephrosis, et al.39 type 2; 538 had GDM or ventricular septal defect; regular insulin-treated 7.9% had tetralogy, hydronephrosis, or ambiguous genitalia; lispro-treated 6.6% had meningo- myelocoele

Masson et al.42 76 Type 1 76 0 4 CM: 1 Down’s syndrome, 1 systolic murmur, 1 deformed hand with absent radius, and 1 polydactyly

Diamond and 2 Type 1? 2 Patient 1: TAB at 20 weeks’ gestation for Kormas54 embryopathy, multiple fetal abnormalities Patient 2: Infant deceased at 3 weeks of age; Diaphragmatic hernia into chest and bilateral undescended testes

Idama et al.55 7 Type 1 7 No congenital abnormalities

Scherbaum et al.56 60 Type 1? 33 27 Lispro-treated: 1 SAB, 1 TAB due to multiple malformations; 1 heart malformation; 1 hyaline membrane syndrome Regular insulin–treated: 1 dysplastic hip CM, congenital malformations; SAB, spontaneous abortion; TAB, therapeutic abortion.

Table 6. Neonatal Macrosomia During Pregnancy Treated With Lispro

Studies Pregnancies Type of Nondiabetic Insulin Outcome (n) diabetes Lispro Regular

Evers et al.60 289 Type 1 11 Increased frequency of macrosomia with lispro

Ozcan et al.59 50 GDM 21 29 Less frequent macrosomia with lispro

Mecacci et al.40 49 GDM 50 25 24 No increased frequency of macrosomia with lispro CM, congenital malformations; SAB, spontaneous abortion; TAB, therapeutic abortion.

incidence of congenital anomalies fetal or neonatal abnormalities were glargine is excreted in breast milk. among neonates whose mothers had identified in either group. However, because human insulin is been treated with lispro during gesta- The studies in Table 6 have evaluat- excreted in human milk, caution has tion (Table 5).39,41,42 ed the incidence of neonatal macroso- been recommended for nursing moth- Macrosomia and analogs. Placental mia among women treated with lispro ers who are using glargine.62 transfer of insulin can occur when compared with human regular insulin. There have been many case reports insulin becomes bound with immuno- There are no controlled human in which pregnant women with globulin,13,57 thereby contributing to studies of glargine use during pregnan- diabetes were treated with glargine. excess fetal growth and development cy. The effect of glargine in pregnancy Table 7 summarizes the outcomes of of macrosomia. In addition, lispro has has only been evaluated in animal those reports. Although glargine may not been detected in cord blood at studies in which toxicological effects improve control compared to NPH, it delivery.58 A study by Jovanovic et al.38 were seen at doses that were seven is not possible to determine the frequen- compared 19 women with GDM treat- times the highest human dose of both cy of macrosomia from these reports. ed with lispro with 22 women with glargine and NPH insulin.61 These There have been no clinical trials in GDM treated with human regular effects resulted from the hypoglycemia human pregnancy treated with insulin. Although anti-insulin antibod- that both insulins induced. There detemir, the other long-acting insulin ies were similar in the two maternal appeared to be no effect on reproduc- analog, although clinical trials are in groups, lispro was nondetectable in tion or embryo-fetal development the early stages. Animal studies for the cord blood, suggesting that it does among the studies conducted in rats.61 embryotoxicity and teratogenicity have not cross the placenta. In addition, no In addition, it is not known whether not demonstrated any difference 98 Diabetes Spectrum Volume 20, Number 2, 2007 Fr

Table 7. Use of Long-Acting Insulin Glargine in Pregnancy Pregnancy and Diabetes / om Research Practice to

Studies n Type of diabetes Treatment with glargine Outcome

Woolderink et al.64 7 Type 1 5 treated throughout Delivered at 37-40 weeks pregnancy; 2 began Birth weight 4,180 g (2,475–4,675 g) glargine in second trimester A1C 6.4% (5.2–8.1%) No congenital malformations

Graves et al.65 4 GDM ? trimester 1 LGA neonate 1 patient with daytime hypoglycemia No cases of nocturnal hypoglycemia

Dolci et al.48 1 Type 1 and second trimester Compared to NPH in first trimester, Addison’s disease better control with glargine

Di Cianni et al.63 5 Type 1 first trimester No congenital malformations

Devlin et al.47 1 Type 1 second and third trimester Better glycemic control with glargine than NPH

Holstein et al.46 1 Type 1 first, second, and third trimester Better glycemic control with glargine than NPH

Torlone et al.21 6 Type 1 first, second, and third trimester Normal outcome

Carrona et al.66 1 Type 1 first, second, and third trimester 3,540-g male infant CM, congenital malformations; SAB, spontaneous abortion; TAB, therapeutic abortion. between detemir and NPH insulin. basal insulin that has been adequately 6De Veciana MD, Major CA, Morgan MA, Asrat Although it is clear that human insulin studied in pregnancy. The long-acting T, Toohey JS, Lien JM, Evans AT: Postprandial versus preprandial blood glucose monitoring in and all of the rapid-acting insulin insulin analogs do not yet have suffi- women with gestational diabetes mellitus requir- analogs appear in milk directly propor- cient safety evaluation in clinical studies ing insulin therapy. N Engl J Med tional to the serum levels of insulin or to warrant their use during pregnancy. 333:1237–1241, 1995 insulin analog achieved in the maternal In addition to diet and lifestyle mod- 7Walkinshaw SA: Pregnancy in women with pre- bloodstream, it is currently unknown ifications, the treatment algorithm in existing diabetes: management issues. Sem Fetal whether detemir is excreted in breast Table 1 is the currently recommended Neonatal Med 10:307–315, 2005 milk. 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Diabetes Res Clin Pract Exp Clin Endocrinol Diabetes 110:6–9, 2002 58:115–121, 2002 57 29Yki-Jarvinen H, Dressler A, Ziemen M, the Menon RK, Cohen RM, Sperling MA, Cutfield HOE 901/3002 Study Group: Less nocturnal 42Masson EA, Patmore JE, Brash PD, Baxter M, WS, Mimouni F, Khoury JC: Transplacental pas- hypoglycemia and better post-dinner glucose Caldwell G, Gallen IW, Price PA, Vice PA, sage of insulin in pregnant women with insulin- control with bedtime insulin glargine compared Walker JD, Lindow SW: Pregnancy outcome in dependent diabetes mellitus: its role in fetal with bedtime NPH insulin during insulin combi- type 1 diabetes mellitus treated with insulin macrosomia. N Engl J Med 323:309–315, 1990 nation therapy in type 2 diabetes. Diabetes Care lispro (Humalog). Diabet Med 20:46–50, 2003 58Boskovic R, Feig DS, Derewlany L, Knie B, 23:1130–1136, 2000 43Loukovaara S, Immonen I, Teramo KA, Kaaja Portnoi G, Koren G: Transfer of insulin lispro 30Raskin P, Klaff L, Bergenstal R, Halle J-P, R: Progression of retinopathy during pregnancy across the human placenta. Diabetes Care Donley D, Mecca T: A 16-week comparison of in type 1 diabetic women treated with insulin 26:1390–1394, 2003 the novel insulin analog insulin glargine (HOE lispro. Diabetes Care 26:1193–1198, 2003 59Ozcan T, Karne A, Murphy J, Nickless N, 901) and NPH human insulin used with insulin 44Cypryk K, Sobczak M, Pertynska-Marczewska Magriples U, Jones DC: Does lispro improve lispro in patients with type 1 diabetes. Diabetes blood glucose control and birth weight? Care 23:1666–1671, 2000 M, Zawodniak-Szalapska M, Szymczak W, Wilczynski J, Lewinski A: Pregnancy complica- [Abstract] Obstet Gynecol 97:S41, 2001 31 Rosenstock J, Schwartz SL, Clark CM, Park tions and perinatal outcome in diabetic women 60Evers IM, De Valk HW, Mol BWJ, Ter Braak GD, Donley DW, Edwards MB: Basal insulin treated with Humalog (insulin lispro) or regular EWMT, Visser GHA: Macrosomia despite good therapy in type 2 diabetes 28-week comparison human insulin during pregnancy. Med Sci Monit glycaemic control in type 1 diabetic pregnancy: of insulin glargine (HOE 901) and NPH insulin. 10:129–132, 2004 results of a nationwide study in the Netherlands. 100 Diabetes Spectrum Volume 20, Number 2, 2007 Diabetologia 45:1484–1489, 2002 first weeks of pregnancy in five type 1 diabetic a case study. Acta Biomed Ateneo Parmense Fr women. Diabetes Care 28:982–983, 2005 77:24–26, 2006 61Hofmann T, Horstmann G, Stammberger I: Pregnancy and Diabetes / om Researchto Practice Evaluation of the reproductive toxicity and 64Woolderink JM, van Loon AJ, Storms F, De 67Levemir (insulin detemir [rDNA origin] injec- embryotoxicity of insulin glargine (Lantus) in Heide L, Hoogenberg K: Use of insulin glargine tion) prescribing information. Bagsvaerd, rats and rabbits. Int J Toxicol 21:181–189, 2002 during pregnancy in seven type 1 diabetic Denmark, A/S, 2005 women. Diabetes Care 28:2394–2395, 2005 62Lantus (insulin glargine [rDNA origin] injec- tion) product information. Bridgewater, N.J., 65Graves DE, White JC, Kirk JK: The use of Angelina L. Trujillo, MD, is an internal Sanofi-Aventis U.S., 2006 insulin glargine with gestational diabetes melli- medicine and endocrinology specialist tus. Diabetes Care 29:471–472, 2006 63Di Cianni G, Volpe L, Lencioni C, and a senior scientist at the Sansum Chatzianagnostou K, Cuccuru I, Ghio A, Benzi 66Caronna S, Cioni F, Dall’aglio E, Arsenio L: Diabetes Research Institute in Santa L, Del Prato S: Use of insulin glargine during the Pregnancy and the long-acting insulin analogue: Barbara, Calif.

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