Use of glargine in pregnant women with Type 1 diabetes mellitus: A case-control study

Clinical Therapeutics/Volume 30, Number 8, 2008

BriefReport Use of Glargine in Pregnant Women with Type 1 Diabetes Mellitus: A Case-Control Study Maria R Imbergamo, MD; Marco C. Amato, MD; Giovanna Sciortino, MD; Massimo Gambina, MD; Maria Accidenti, MD; Angela Criscimanna, MD; Carla Giordano, MD; and Aldo Galluzzo, MD

Section of Endocrinology, Departmentof Experimental Oncologyand ClinicalAppfications (DOSAC), Facultyof Medicine, Universityof Palermo, Palermo, Italy ABSTRACT Background: Insulin glargine is a once-daily basal insulin analog with prolonged duration of action and absence of an evident peak. Glargine is associated with reduced frequency of hypoglycemic episodes (mostly nocturnal) as well as effective glycemic control. Maintenance of good metabolic control before conception and throughout pregnancy is essential to lower the risk of fetal malformations. Glargine might be a valuable alternative in the management of pregnancies complicated by diabetes mellitus. However, because its clinical utility has not been established, the use of glargine is not currently recommended during pregnancy. Objective: The aim of this study was to retrospectively evaluate (years 2004-2007) the effectiveness and safety of insulin glargine compared with neutral protamine Hagedorn (NPH) in women affected by type 1 diabetes mellitus (TIDM) during pregnancy. Methods: The study comprised pregnant women affected by TIDM who were followed up in the Diabetes and Pregnancy Outpatient Clinic at the University of Palermo, Palermo, Italy, within 8 -+ 3.4 weeks subsequent to a positive pregnancy test. All patients with TIDM were treated with conventional basal-bolus insulin therapy (aspart or lispro analogs at the 3 main meals plus glargine or NPH at bedtime). Healthy pregnant women were used as controls for fetal and neonatal parameters. Patients were consecutively enrolled. In all women, metabolic status was determined daily by mean glycemic values (2-hour postprandial blood glucose) and glycosylated hemoglobin (HbAlc) values (at 3-month intervals). Fetal measurements (<50th and >90th centiles of the head circumference, abdomen circumference, and femoral length) were 1476

evaluated by ultrasound at second and third trimesters. Weight and femoral length were assessed at birth, and neonates were classified according to the fetal growth curve for the Italian population (<10th centile = small for gestational age; and >90th centile = large for gestational age (LGA). Results: A total of 73 pregnant women (30 with TIDM and 43 healthy [control]) were included in the study. Of the 30 diabetic pregnant women included in the study, 15 (mean [SD] age, 27.4 [5.2] years; mean pregravidic weight, 59.7 [11.7] kg) maintained their preconception therapy with glargine, and 15 (mean age, 30.1 [2.4] years; mean pregravidic weight, 60.7 [8.7] kg) with NPH. No significant difference was observed between the glargine-treated group and the NPH-treated group with regard to pregravidic hypertension, third-trimester preeclampsia, maternal complications and/or their progression during pregnancy (diabetic retinopathy, micro- or macroalbuminuria) and episodes of mild hypoglycemia, severe hypoglycemia, and ketosis. There were no significant betweengroup differences in insulin requirements (IU/kg of body weight) and glycemic profile, with the exception of better fasting and 2 hours after breakfast glycemic values in the glargine group during the first (P = 0.008 and P < 0.001, respectively) and the second (P = 0.015 and P = 0.016) trimesters, confirmed by the lower HbAlc levels in the first trimester (P = 0.037). The frequency of femoral length <50th centile at both second and third trimesters was 4/15 (26.7%) in the Accepted for pubficationJune 23, 2008. doi:l 0.1016/j.clinthe ra.2008.08.013 0149-2918/$32.00 © 2008 Excerpta Medica Inc. All rights reserved.

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glargine-treated group (P = 0.033 and P = 0.013, respectively, vs control), 3/15 (20.0%) and 1/15 (6.7%), respectively, in the NPH-treated group (both, P = NS vs control), and 2/43 (4.7%) and 1/43 (2.3%), respectively, in the control group. The prevalence of LGA was 7/15 (46.7%) in the glargine group (P < 0.001 vs control), 4/15 (27.6%) in the NPH group (P = 0.033 vs control), and 2/43 (4.7%) in the control group. Conclusions: Although our retrospective study involved only a small number of participants, no significant difference was found in glycemic control between glargine and NPH treatments. Use of glargine was associated with a significantly higher frequency of femoral length <50th centile. Further larger prospective studies are necessary to assess the safety profile of glargine in T I D M during pregnancy. (Clin Ther. 2008;30: 1476-1484) © 2008 Excerpta Medica Inc. Key words: diabetes type 1, glargine, pregnancy, neonatal outcome.

INTRODUCTION Insulin glargine is a once-daily basal insulin analog with prolonged duration of action and absence of an evident peak. 1 Glargine is associated with reduced frequency of hypoglycemic episodes (mostly nocturnal) as well as effective glycemic control, e,3 Maintenance of good metabolic control before conception and throughout pregnancy is essential to lower the risk of fetal malformations. 4-7 However, some doubts still exist surrounding glargine's mitogenic action due to the modification in the C-term site of the insulin B chain, which enhances the affinity for insulin growth factor 1 (IGF-1) receptor. 8 Animal studies 9,1° have not detected direct harmful effects with respect to pregnancy, embryonal/fetal development, parturition, or postnatal development. With regard to human studies, a limited number of postmarketing surveillance studies have not reported significant adverse effects of insulin glargine on pregnancy or on the health of the fetus and newborn child. However, because there is limited data regarding its clinical utility, glargine is not currently recommended during pregnancy. 11-17 Furthermore, maternal insulin requirement (IR), birth weight, and detailed metabolic evaluation have not been reported.18 Recently, 2 studies on pregnant women with type 1 diabetes mellitus (TIDM) treated with glargine were published: a survey study > on 115 pa-

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tients and a retrospective study e° on 13 patients. Although they did not describe any major adverse outcome for the babies or the mothers, the ultrasound evaluations of fetal parameters were not reported. In addition, they were not case-control studies. The aim of this study was to report a case-control study in which we retrospectively investigated neonatal outcomes and maternal metabolic parameters in pregnant women affected by T I D M treated with insulin glargine or neutral protamine Hagedorn (NPH) compared with healthy controls. PATIENTS A N D M E T H O D S

Pregnant women with T I D M who were followed up in the Diabetes and Pregnancy Outpatient Clinic at the University of Palermo, Palermo, Italy (2004-2007), within 8 -+ 3.4 weeks subsequent to a positive pregnancy test were included in the study. All patients were treated with conventional basal-bolus insulin therapy (glargine or NPH) (aspart or lispro analogs at the 3 main meals and at bedtime). A portion of the patients continued glargine insulin treatment (preconception therapy) before the commencement of the study (all within 8 -+ 3.4 weeks from amenorrhea), while the remaining patients were maintained on NPH. Patients who were transferred to other hospitals during pregnancy or follow-up, those who did not give their consent to continue glargine during pregnancy and therefore switched to NPH, and those who had spontaneous miscarriages during the first trimester were excluded from the study. Healthy pregnant age- and weight-matched women were selected from our Diabetes and Pregnancy Outpatient Clinic's database and used as controls. The medical staff at the Diabetes and Pregnancy Outpatient Clinic at the University of Palermo consisted of an obstetrician, a diabetologist, and a neonatologist. In accordance with the American Diabetes Association, 21 we evaluated the following maternal parameters in all pregnant women: age; week modality of delivery; weight before and at term of pregnancy (A weight); diagnosis of hypertension before pregnancy; onset of hypertension during pregnancy; and preeclampsia in the third trimester (coexistence of hypertension, edemas, and proteinuria). In women with TIDM, we also evaluated the following: duration of diabetes; presence/absence of complications such as retinopathy and nephropathy and their progression during pregnancy; mild or severe maternal 1477

Clinical Therapeutics

hypoglycemia; rate of recurrence of maternal ketosis; glycosylated hemoglobin (HbAlc) levels (via highperformance liquid chromatography at the time of the first observation and then during each trimester); fasting and postprandial blood glucose levels (2 hours after consumption of the 3 main meals [breakfast, lunch, and dinner]); and IR (calculated separately at each trimester for rapid analogs [aspart or lispro] and glargine or NPH). With regard to fetal and neonatal parameters, in both diabetic and control women, we assessed: neonatal weight and length; head circumference (HC); abdominal circumference (AC) and femoral length at second and third trimesters (20-22 and 30-33 weeks, respectively). All neonates were classified according to the fetal growth curve for the Italian population, ee which indicated small for gestational age when weight was <10th centile, normal for gestational age when weight was between 10th and 90th centiles, and large for gestational age (LGA) when weight was >90th centile. Congenital abnormalities, neonatal hypoglycemia, neonatal respiratory adaptation (NRA), respiratory distress syndrome (RDS), neonatal hypocalcemia, and neonatal jaundice were also evaluated. The Apgar test e3 was conducted at 1 and 5 minutes. An Apgar score <6 was considered low and a score between 7 and 10 was considered normal. In T I D M patients, we also performed (by fetal echocardiography) the evaluation of the interventricular septal thickness (IVST) at 20 and 32 weeks of gestation. This retrospective study was approved by the Institutional Review Board of the Faculty of Medicine of the University of Palermo, Palermo, Italy. All TIDM patients gave their informed consent to continue their preconception therapy and none of the women with TIDM received ex novo glargine therapy during pregnancy.

Statistical Analysis Statistical analysis was performed using SPSS 11 software, Windows Edition (SPSS Inc., Chicago, Illinois). Continuous data were analyzed as mean (SD). Rates and proportions were calculated for categoric data. As continuous variables were without normal distribution, we used nonparametric tests and differences were analyzed by the Mann-Whitney U test. For categoric variables, differences were analyzed by Ze test and Fisher exact test when appropriate. P < 0.05 was considered statistically significant. > A power analysis of this study was not conducted. 1478

RESU LTS A total of 73 pregnant women (race, white; mean [SD] age, 27.5 [5.5] years; mean [SD] pregravidic weight, 64 [13.9] kg) were included in the study. Thirty women were affected with TIDM. Of this number, 15 received glargine therapy (mean [SD] age, 27.4 [5.2] years; IR = 0.22 [0.05] IU/kg of body weight [BW]), and 15 received NPH therapy (mean age, 30.1 [2.4] years; IR = 0.24 [0.04] IU/kg of BW). The remaining 43 women (mean age, 26.7 [6.2] years) were healthy and served as controls. No statistical difference was observed between the glargine group and the NPH group with regard to age, duration of disease, week and modality of delivery, weight before and at term of pregnancy, or complications (Table I). The duration of pregnancy was significantly shorter in the diabetic (TIDM) patients compared with the control (glargine group: mean [SD] 36.4 [2.2]; NPH group: 37 [1.3]; control: 39.5 [1.2] weeks, respectively; P < 0.001). Prevalence of elective cesarean section e5 was significantly higher in T I D M patients than in the control (100% vs 60.4%; P < 0.001). With regard to the mean weight gain during pregnancy (k weight), a significant statistical difference was observed between T I D M patients and the control (glargine group compared with control: mean [SD] 12.4 [3.8] vs 9.3 [5.1] kg, P = 0.035; NPH group compared with control: 13.5 [3.9] vs 9.3 [5.1] kg, P = 0.007), while no significant difference was found between the glargine- and the NPH-treated groups (Table I). No significant difference was observed between the glargine and NPH groups with regard to pregravidic hypertension, third-trimester preeclampsia, maternal complications and/or their progression during pregnancy (diabetic retinopathy, micro- or macroalbuminuria), and episodes of mild hypoglycemia, severe hypoglycemia, and ketosis (Table I). Although the glargine group had significantly lower lispro- or aspart-IR compared with the NPH group (P = 0.018, P = 0.050, and P = 0.041 in first, second, and third trimesters, respectively), no difference was found between the glargine and NPH groups in relation to total IR (Table II). The glargine group had significantly lower values of HbAlc at the end of the first trimester (P = 0.037, glargine vs NPH) and lower blood glucose levels both in fasting conditions during the first and second trimesters and 2 hours after breakfast during the first and second trimesters (P = 0.008, P = 0.015, P < 0.001, and P = 0.016, respecVolume 30 Number 8

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Table I. Maternal parameters and complications in 30 pregnant women with type 1 diabetes mellitus. Data are no. (%) unless otherwise specified. Glargine (n = 1.5)

Variable Maternal parameters in women with type 1 diabetes mellitus Age, mean (SD), y Duration of diabetes, mean (SD), y Week of delivery, mean (SD) Pregravidic weight, mean (SD), kg Postpregnancy weight, mean (SD), kg A Weight, mean (SD) Modality of delivery Normal vaginal delivery Elective cesarean section Emergency cesarean section Pregravidic hypertension Gravidic hypertension Third-trimester preeclampsia

27.40 (5.15) 14.46 (6.86) 36.42 (2.21) 59.67 (11.69) 72.10 (10.44) 12.42 (3.84)

Maternal complications and their progression during pregnancy Diabetic retinopathy Nonproliferant Proliferant Worsening of retinopathy Microalbuminuria Macroalbuminuria Worsening of microalbuminuria Mild hypoglycemia Sporadic Frequent Severe hypoglycemia Frequent episodes of ketosis

15 (100)

NPH (n = 1.5)

30.13 16.13 37.04 60.66 74.12 13.46

(2.35) (4.35) (1.27) (8.06) (10.56) (3.88)

p*

0.067 0.486 0.838 0.539 0.624 0..539

15 (100)

I(6.7) 4 (26.7) I(6.7)

4 (26.7) -

1.000 1.000 1.000

2 (13.3) 2 (13.3) 1 (6.7) 2 (33.3) I(6.7)

5 1 2 1

(33.3) (6.7) (13.3) (6.7)

0.403

9 (60.0) S (33.3) I(6.7) 2 (13.3)

8 (53.3) 7 (46.7) 3 (20)

0.498

1.000 0.475

1.000 1.000

NPH = neutral protamine Hagedorn. *Significant values when P < 0.05.

tively). No significant difference was found in regard to other metabolic parameters (Table II). In the glargine group, 7/15 (46.7%) neonates were classified as LGA, while 4/15 (26.7%) in the NPH group were classified accordingly (P = NS). When compared with the control group, the prevalence of LGA was significantly higher in both the glargine (7/15 [46.7%] vs 2/43 [4.6%]; P < 0.001) and the NPH groups (4/15 [26.7%] vs 2/43 [4.6%]; P = 0.033). The evaluation of HC and AC during the second and third trimesters did

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not suggest any statistically significant difference among the glargine, NPH, and control groups (Table HI). Femoral length observed in the second trimester suggested a significantly higher frequency of <50th centile cases in the glargine group compared with the control group (4/15 [26.7%] vs 2/43 [4.6%]; P = 0.033), whereas no significant difference was observed between the NPHtreated group and the control group (3/15 [20%] vs 2/43 [4.6%]; P = NS). The difference was also confirmed at the third trimester (glargine vs control: 4/15 [26.7%] vs

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Table II. Metabolic parameters in 30 pregnant women with type 1 diabetes mellitus. Data are mean (SD). Glargine Group (n = 15)

NPH Group (n = 15)

P

Lispro or aspart requirement First trimester Second trimester Third trimester

0.44 (0.13) 0.47 (0.11) 0.59 (0.17)

0.58 (0.16) 0.59 (0.17) 0.72 (0.16)

0.018" 0.050* 0.041"

Glargine or NPH requirement First trimester Second trimester Third trimester

0.28 (0.07) 0.29 (0.09) 0.34 (0.10)

0.26 (0.13) 0.27 (0.11) 0.31 (0.13)

0.561 0.436 0.512

Total insulin requirement First trimester Second trimester Third trimester

0.72 (0.16) 0.77 (0.16) 0.89 (0.21)

0.84 (0.24) 0.86 (0.21) 0.99 (0.19)

0.134 0.116 0.217

7.40 (0.88)

6.23 (0.86)

8.20 (1.40) 7.79 (1.13) 6.62 (0.80) 6.47 (0.95)

0.126 0.037* 0.161 0.461

Fasting glucose, mmol/L First trimester Second trimester Third trimester

7.54 (2.22) 6.83 (1.41) 7.05 (1.55)

11.14 (4.00) 9.17 (2.80) Z96 (2.22)

0.008* 0.015" 0.305

2 Hours after breakfast glucose, mmol/L First trimester Second trimester Third trimester

5.68 (1.75) 5.68 (1.49) 5.98 (1.19)

8.80 (2.29) 7.02 (1.45) 6.91 (1.77)

<0.001" 0.016" 0.137

2 Hours after lunch glucose, mmol/L First trimester Second trimester Third trimester

8.03 (1.79) 6.30 (1.47) 6.39 (1.16)

7.24 (2.14) 7.43 (1.58) 7.05 (1.43)

0.486 0.067 0.250

6.56 (2.02)

8.94 (2.53) 7.34 (1.24) Z30 (1.79)

0.011 0.653 0.512

Variable

H bAle, % At conception First trimester Second trimester Third trimester

2 Hours after dinner glucose, mmol/L First trimester Second trimester Third trimester

6.86 (0.95) 6.16 (0.67)

Z24 (2.39) 6.93 (1.41)

NPH = neutral protamine Hagedorn; HbAlc = glycosylated hemoglobin. *Significant values when P < 0.05.

1/43 [2.3%], P = 0.013; NPH vs control: 1/15 [6.7%] vs 1/43 [2.3%], P = NS). No significant difference in IVST alterations was observed between the glargine and NPH groups (Table HI). No cases of perinatal deaths or congenital abnormalities (Table W) were observed. No statistically significant difference was observed in the

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neonatal parameters hypoglycemia, NRA, RDS, hypocalcemia, jaundice, or Apgar scores (Table W). DISCUSSION As reported in several studies, 7,21,26,27 optimal glycemic control (achieved through strict self-monitoring of

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Table III. Fetal and neonatal outcomes in retrospective case-control study in pregnant women with type 1 diabetes mellitus. Data are no. (%) unless otherwise specified. Glargine Group (n = 15)

NPH Group (n = 15)

Control Group (n = 43)

P*

Pt

Neonatal weight, mean (SD), g

3278 (756)

3503 (455)

3273 (372)

0.683

0.419

0.116

Neonatal length, mean (SD), cm

49.03 (2.90)

49.02 (1.92)

49.02 (1.92)

0.512

0.565

0.993

2 (4.65)

0.449

<0.001~

0.033~

9 (20.93)

-

0.094

0.094

LGA SGA

7 (46.67) -

4 (26.67) -

pt

HC second trimester <50th Cenule >90th Cenule

3 (20.0) 2 (13.3)

4 (26.7) -

5 (11.6) 10 (23.3)

1.000 0.482

0.413 0.712

0.217 0.052

HC third trimester <50th Cenule >90th Cenule

2 (13.3) 3 (20.0)

1 (6.7) 2 (13.3)

3 (7.0) 9 (20.9)

1.000 1.000

0.596

1.000

1.00 0.710

AC second trimester <50th Cenule >90th Cenule

3 (20.0) 2 (13.3)

1 (6.7) 1 (6.7)

3 (7.0) 6 (14.0)

0.597 1.000

0.172 1.000

0.663

AC third trimester <50th Cenule >90th Cenule

2 (13.3) 4 (26.7)

4 (26.7)

6 (14.0) 7 (16.3)

0.482 1.000

1.000 0.450

0.323 0.450

FL second trimester <50th Cenule >90th Cenule

4 (26.7) 1 (6.7)

3 (20.0) 3 (20.0)

2 (4.7) 13 (30.2)

1.000 0.597

0.033~ 0.086

0.103 0.522

FL third trimester <50th Cenule >90th Cenule

4 (26.7) 2 (13.3)

1 (6.7) 1 (6.7)

1 (2.3) 5 (11.6)

0.329 1.000

0.013§ 1.000

0.453 1.000

IVST 20th week <50th Cenule >90th Cenule

4 (26.7) -

-

0.099

3 (20.0)

2 (13.3)

-

0.482

5 (33.3)

-

1.000

IVST 32nd week <50th Cenule >90[h Cen[ile

5 (33.3)

1.000

0.224

-

NPH = neutral protamine Hagedorn; LGA = large for gestational age; SGA = small for gestational age; HC = head circumference; AC = abdominal circumference; FL = femoral length; IVST = interventricular septal thickness. *Glargine versus NPH. f Glargine versus control. t NPH versus control. §Significant values when P < 0.0S.

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Clinical Therapeutics blood glucose levels, use of intensive insulin regimen benefiting from new insulin analogs or pump devices) is critical for the management of pregnancy in T I D M women. Glargine, when compared with conventional long-acting insulins, has been associated with improved glycemic control and fewer hypoglycemic events in both type 1 and type 2 diabetes. 2,27-29 Therefore, the use of insulin glargine in the management of pregnancy complicated by diabetes has been proposed. This retrospective case-control study suggests that the use of glargine during pregnancy in T I D M patients was not significantly different in effectiveness or tolerability from NPH. Despite the fact that glargine IR was significantly lower than NPH IR, total IR (accounting also for the analog IR) was not different in the 2 groups, as was the case with maternal weight. With regard to glycemic status, significantly lower HbAlc (P = 0.037), lower fasting glucose (P = 0.008), and lower 2 hours after breakfast blood glucose levels (P < 0.001) were observed in the glargine group during the first trimester. These findings might be due to the longer duration of action of glargine.1 However, because this finding was significant only in the first trimester, it might suggest that NPH may be equally effective during pregnancy, a period character-

ized by physiologic reduction in insulin sensitivity and higher compliance in diabetic women. 3°-35 Conversely, the difference in glycemic control during the first trimester might be due to lower insulin adjustment requirements during treatment with glargine in a period of relatively better insulin sensitivity. Nevertheless, it should be noted that HbAlc levels, mirroring the global glycemic status, were optimal in both groups. Contrary to what has been reported elsewhere, 2,1°-17 this study did not find a lower incidence of hypoglycemic events for glargine compared with NPH. The frequency of ketosis was not significantly different as well. The higher incidence of LGA observed in the glargine group compared with the control group (7/15 [46.7%] vs 2/43 [4.7%]; P < 0.001) seemed to support the finding that the glargine molecule has stronger affinity for the IGF-1 receptor in vitro, 8 but as this was also observed in the NPH group compared with the control group (4/15 [26.7%] vs 2/43 [4.7%]; P = 0.033]), the effect might be due to diabetes itself rather than to specific treatment. Among the fetal parameters examined, we observed a higher prevalence of femoral length <50th centile during the second (P = 0.033) and third (P = 0.013) trimesters in the glargine

Table IV. Neonatal outcomes in retrospective case-control study in pregnant women with type 1 diabetes mellitus. Data are no. (%).

Congenital abnormalities

Glargine Group (n = 15)

NPH Group (n = 15)

-

1 (6.7)

-

Neonatal hypoglycemia

4 (26.7)

0.330

Neonatal respiratory a d a p t a t i o n

1 (6.7)

-

0.483

Respiratory distress syndrome

3 (20.0)

-

0.224

Neonatal hypocalcemia

3 (20.0)

-

0.224

Neonatal jaundice

2 (13.3)

-

0.483

1 - M i n A p g a r score 7-10 _<6

11 (73.3) 4 (26.7)

15 (100) -

0.099

5 - M i n A p g a r score 7-10 _<6

11 (73.3) 4 (26.7)

15 (100) -

0.099

NPH = neutral protamine Hagedorn.

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M.P. Imbergamo et al. g r o u p c o m p a r e d with the control group. This finding had not been previously reported, and although it did not affect the final neonatal length, it is w o r t h y of conducting further r a n d o m i z e d prospective studies on larger cohorts of diabetic p r e g n a n t w o m e n treated with glargine. The femoral length <50th centile on the basis of metabolic p a r a m e t e r s c a n n o t be explained. N o published data are available with regard to experimental models involving glargine actions. To this regard, glargine should act, at least theoretically, to increase and not to decrease, as in our o w n case, femoral length, because of its characteristics of enhanced affinity for the IGF-1 receptor. 8 For this reason, these data need to be confirmed in prospective studies in larger cohorts of T 1 D M p r e g n a n t w o m e n . Studies 5,6 have reported that there is an increased prevalence of congenital anomalies and s p o n t a n e o u s a b o r t i o n in diabetic w o m e n w h o have p o o r glycemic control during the period of fetal organogenesis, which is nearly complete at 7 weeks after conception has t a k e n place. Unfortunately, a w o m a n m a y not even k n o w she is p r e g n a n t at this time, as in our case. Because organogenesis is c o m p l e t e d so early in fetal development, w h e n a w o m a n presents to her health care clinician due to a missed menstrual period by only a few days, the neural tube and bone defects are p r o b a b l y already set, and therefore it m a y be too late for femoral osteogenesis to determine final length. H o w e v e r , if blood glucose levels are n o r m a l i z e d immediately, there still remains the chance to prevent cardiac anomalies.

CONCLUSIONS In our small, retrospective case-control study, no significant difference was found in glycemic control with glargine and N P H treatments. The effectiveness of glargine on glycemic control was not associated with significantly different congenital malform a t i o n s or particularly significant a d v a n t a g e s in c o m p a r i s o n with conventional long-acting insulin therapy. Use of glargine was associated with a significantly higher frequency of femoral length <50th centile. Further larger prospective studies are necessary to assess the safety profile of glargine in T 1 D M during pregnancy. A C K N O W L E D G M ENT Drs. I m b e r g a m o , A m a t o , and G i o r d a n o contributed equally to this manuscript.

August 2008

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Address correspondence to: C a r l a G i o r d a n o , MD, Section of Endocrinology, Department of Experimental Oncology and Clinical A p p l i c a t i o n s , U n i v e r s i t y of P a l e r m o , P i a z z a delle C l i n i c h e 2, 9 0 1 2 7 P a l e r m o , Italy. E - m a i l c g i o r d a n @ u n i p a . i t

Volume 30 Number 8