CLINICAL OBSTETRICS AND GYNECOLOGY Volume 56, Number 4, 816–826 r 2013, Lippincott Williams & Wilkins

Insulin Analogues in the Treatment of Gestational Diabetes Mellitus CELESTE P. DURNWALD, MD Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania Abstract: Rapid-acting insulin analogues are the preferred choice for short-acting insulin due to their superior pharmacologic profiles, leading to greater flexibility and convenience of dosing. This has lead to greater patient satisfaction and improved quality of life. Clinical experience with rapid-acting insulin analogues in pregnancy is increasing. Currently, there is limited data available on the use of long-acting insulin analogues in pregnancy. The focus of this review is to discuss the role of insulin analogue therapy in the treatment of the woman with gestational diabetes. Key words: insulin analogues, gestational diabetes, insulin lispro, insulin aspart, insulin glargine, insulin detemir

Insulin Therapy in Women With Gestational Diabetes Mellitus (GDM) The mainstay of GDM management is dietary intervention. Approximately 50% Correspondence: Celeste P. Durnwald, MD, Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, The University of Pennsylvania, Philadelphia, PA. E-mail: celeste.durnwald@uphs. upenn.edu The author declares that there is nothing to disclose. CLINICAL OBSTETRICS AND GYNECOLOGY

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of women will meet target values for glucose control within the first 2 weeks of dietary therapy, but only an additional 10% will achieve euglycemia by the fourth week.1 Most clinicians use these general guidelines to determine dietary failure as to when to initiate pharmacologic therapy. In the majority of GDM women, insulin injections remain the gold standard for treatment of those who fail to achieve euglycemia on dietary management alone. Institution of strict glycemic control has been demonstrated to reduce neonatal morbidity and mortality associated with the diabetic pregnancy by decreasing the incidence of stillbirth and macrosomia.2,3 Infants born to well-controlled diabetic women also have fewer neonatal complications such as respiratory distress syndrome, hypoglycemia, and hyperbilirubinemia.4 Insulin replacement is designed to mimic the normal physiological release of insulin by the pancreas. Women with GDM have endogenous insulin production, but are unable to mount the 2- to 3-fold increase in insulin secretion required to maintain VOLUME 56

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Insulin Analogues in GDM euglycemia related to diabetogenic placental hormones. Insulin replacement is typically divided into basal and prandial insulin. Basal insulin is designed to restrain hepatic glucose production between meals and in the fasting state. Prandial insulin reduces glucose excursions associated with feeding. Unlike women with preexisting diabetes, insulin therapy for a woman with GDM is often tailored to address the woman’s individual glucose profile. The prescribed insulin regimen may include as few as 1 and as many as 4 insulin injections. For example, in women with only postprandial glucose elevations, administration of a prandial insulin would be most helpful. In those with isolated fasting glucose elevations, only basal insulin may be necessary.

Insulin Analogues Before the introduction of insulin analogues, women with GDM were treated with the standard insulins, neutral protamine hagedorn (NPH), and regular insulin. Basal insulin therapy for GDM should continue to focus on the use of NPH insulin, an intermediate-acting insulin. In many cases, the greater insulin resistance associated with GDM and subsequent higher insulin requirements cannot be adequately treated with the long-acting insulin analogues (LAIA), glargine and detemir, which are peakless. Conversely, rapid-acting insulin analogues (RAIAs) are now the preferred choice for prandial insulin dosing due to their superior pharmacologic profiles, leading to greater flexibility and convenience of dosing and thus, greater patient satisfaction and improved quality of life. Over the past few years, clinical experience with insulin analogues in pregnancy has increased dramatically. The majority of data on insulin analogue therapy in pregnancy pertains to the treatment of women with preexisting diabetes, most specifically type 1 diabetes. However, the tenets of therapy

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and clinical experience with these newer insulin formulations can be extrapolated to the treatment of women with GDM. Certain aspects of treatment, such as congenital malformation risk, are not as pertinent to GDM because the diagnosis occurs beyond the period of organogenesis. However, transplacental passage, immunogenicity, and clinical efficacy in addition to maternal and neonatal outcomes will be discussed. The purpose of this article is to review recent advances in insulin analogue therapy as it pertains to the treatment of women with GDM.

RAIAs In the treatment of GDM, the mainstay of prandial insulin has been regular insulin. Regular insulin is formulated with the addition of zinc atoms to the solution of dimers which associate to form hexamers. These hexamers diffuse slowly in the circulation. Therefore, it has a slower onset of action, peak action, and a longer duration of action than the newly developed RAIAs. RAIAs are the result of recombinant DNA technology. They quickly dissociate into monomers in the subcutaneous tissue which allows for a shorter onset of action, peak action, and duration of action. Table 1 outlines the duration of action of standard insulins and insulin analogues. The pharmacokinetic and pharmacodynamic properties of RAIAs result in twice the maximum concentration of insulin in approximately half the time compared with regular insulin (Fig. 1), leading to less mean glucose excursion in response to a food bolus and less hypoglycemia between meals. This superior drug profile allows maximum flexibility and convenience in dosing resulting in greater patient satisfaction and improved quality of life.5 Thus, insulin analogues have emerged as the preferred choice for prandial insulin. www.clinicalobgyn.com

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TABLE 1.

Pharmacologic Profiles of Standard Insulins and Insulin Analogues Onset of Action

Standard Regular Neutral protamine hagedorn Rapid-acting analogues Lispro Aspart Glulisine Long-acting analogues Glargine Detemir

Peak Action

Duration of Action (h)

30-60 min 2-4 h

2-3 h 4-10 h

8-10 12-18

5-15 min 5-15 min 5-15 min

30-90 min 30-90 min 30-90 min

4-6 4-6 4-6

2-4 h 3-4 h

None None

20-24 20

Insulin Lispro Insulin lispro, approved by the FDA in 1996, is the most studied insulin analogue in pregnancy. Insulin lispro is the result of a modification of the b-chain of human insulin by inversion of lysine from position B29 to B28 with proline from B28 to B29.

TRANSPLACENTAL PASSAGE/ IMMUNOGENICITY

Insulin can cross the placenta when it complexes with immunoglobulins forming an antigen-antibody complex. Previous studies have linked transplacental

passage of these complexes with fetal overgrowth. Jovanovic et al6 first reported on the immunologic effects and placental transfer of insulin lispro in women with GDM. In this study, antiinsulin antibody levels were similar in both groups, both at enrollment and delivery. Insulin lispro was undetectable in the umbilical cord blood, including 4 women who received continuous intravenous administration of the drug during labor. There were no cases of fetal anomaly, macrosomia, or neonatal hypoglycemia. Two in vitro perfusion studies have been published evaluating transfer of insulin lispro across the human placenta.7,8

FIGURE 1. Pharmacodynamic profile of standard insulin and insulin analogues. NPH indicates neutral protamine hagedorn.

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Insulin Analogues in GDM Boskovic evaluated placental transfer of insulin lispro in term human placentas exposed to a range of insulin lispro concentrations in which the maternal side of the placenta was perfused with constant concentrations of the drug and the fetal circulation was closed. Although there was a possibility of transfer with concentrations mimicking a single subcutaneous dose of over 50 U which was maintained for over 60 minutes, there was no placental transfer at single standard doses.7 Given the half-life of insulin lispro, it is unlikely that this physiological state could be reproduced in the clinical setting. These findings were confirmed on a smaller scale by Holcberg et al.8

CONGENITAL MALFORMATIONS AND FETAL OVERGROWTH

Most early diagnoses of GDM, especially in the first trimester, represent women with previously undiagnosed preexisting diabetes. However, in the rare case of early screening and diagnosis of GDM, the topic of congenital malformation risk will be discussed briefly. Over the past 10 years, multiple studies have been published evaluating the use of insulin lispro during pregnancy and the rate of congenital malformations.9–12 The largest of which was a multinational, multicenter retrospective review of 496 women during 533 pregnancies resulting in the birth of 542 infants.12 Women with pre-GDM who were treated with insulin lispro at least 1 month before conception through the first trimester of pregnancy were evaluated. More than 96% of the women remained on insulin lispro for the remainder of the pregnancy. Glycemic control of the population as measured by hemoglobin A1c was 8.9% ± 4.2% at initial visit with a decrease to 6.2% ± 2.4% in the third trimester. Two dysmorphologists reviewed all anomalies and found 27 (5.4%) of the offspring had major congenital malformations and 2 (0.4%) had minor anomalies. This report is consistent

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with the previously published rates of major congenital malformations of 2.1% to 10.9% in women with preexisting diabetes requiring insulin therapy during pregnancy. No study published to date has reported a higher malformation rate than the rates previously established for the pregestational diabetic pregnancy. Insulin lispro has a great homology with insulin growth factor-1 (IGF-1) raising a concern for the possibility of increased growth in fetuses of women treated with this RAIA. With regard to fetal overgrowth, similar rates of macrosomia have been reported in pregnancies treated with insulin lispro and regular insulin.13–16 Table 2 shows the rates of congenital malformations and fetal overgrowth in pregnancies treated with insulin lispro, the majority of which are women with pre-GDM. From the culmination of these reports, insulin lispro is not associated with higher rates of congenital malformations or fetal overgrowth compared with standard insulin therapy. CLINICAL EFFICACY

The superior pharmacologic profile of insulin lispro including the shorter onset of action and twice the maximal peak insulin concentration compared with regular insulin favor improved clinical outcomes with lispro treatment. In the first study of GDM women treated with insulin lispro, areas under the curve for glucose, insulin, and C-peptide were significantly lower in the lispro group than those treated with regular insulin, despite a similar hemoglobin A1c level.6 Women treated with lispro also experienced fewer hypoglycemic episodes defined as symptoms and blood glucose concentration 0.001), but similar A1c levels in both treatment groups in the third trimester.16 www.clinicalobgyn.com

Rates of severe hypoglycemic episodes were similar. Aydin and colleagues evaluated women with both pregestational and GDM treated with insulin lispro and regular insulin. Although mean hemoglobin A1c during pregnancy for the entire population was similar between groups, in the 53 women with GDM, those treated with insulin lispro had lower hemoglobin A1c levels compared with those treated with regular insulin (5.25% ± 0.8% vs. 6.5% ± 2.0%, P = 0.013).13 MATERNAL/NEONATAL OUTCOMES

Two recent studies have evaluated maternal obstetrical outcomes for women with preexisting diabetes undergoing lispro treatment in pregnancy. Both studies have shown similar rates of preeclampsia, preterm birth, and cesarean delivery in those treated with insulin lispro compared with regular insulin.15,16 Similarly, rates of shoulder dystocia, neonatal intensive care unit (NICU) admission, respiratory distress syndrome, and neonatal hypoglycemia were comparable.16 To date, only 1 study has evaluated anthropometric characteristics of newborns exposed to insulin lispro in utero.17 This study enrolled 49 pregnant

Insulin Analogues in GDM women with GDM, randomly assigned to treatment with insulin lispro or regular insulin, and 50 pregnant women with a normal glucose challenge test, matched for age, parity, prepregnancy weight, and body mass index. There was no difference between groups in rate of LGA or SGA infants. However, the rate of infants with a cranialthoracic circumference ratio between the 10th and 25th percentile was significantly less in women treated with insulin lispro compared with regular insulin (12% vs. 37.5%). This rate was comparable with the rate seen in those with normal glucose tolerance (14%). In this study, 1-hour postprandial glucoses in the lispro group were close to the physiological levels as demonstrated by the normal glucose tolerance women. In the regular insulin group, 1-hour postprandial glucoses were higher than both normal glucose tolerance women and those GDM treated with lispro. This may have contributed to the aberration in fetal growth pattern seen in this group. Although interesting, further investigation is needed on a larger scale before any conclusive statements can be made as to whether treatment with insulin lispro is associated with any measurable effect on anthropometric characteristics of the newborn. From the entirety of these studies, it can be concluded that insulin lispro does not offer a clear benefit for improved glycemic control or less hypoglycemia. In contrast, insulin lispro seems to have comparable results to other short-acting insulins for glycemic control in the pregnant diabetic woman with the added advantage of improved patient satisfaction likely related to the flexibility in dosing. Greater patient satisfaction may lead to improved compliance with dosing regimens. Select perinatal outcomes are similar in those women treated with insulin lispro and regular insulin.

Insulin Aspart Insulin aspart is formulated by substituting negatively charged aspartic acid for

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proline in position B28 on the b-chain of human insulin. First approved in 1999, there are a limited number of studies addressing the use of insulin aspart in pregnancy. CLINICAL EFFICACY

In 2003, Pettitt et al18 were the first to study the short-term clinical efficacy of insulin aspart in comparison with regular insulin in 15 women with GDM. Peak insulin and glucose concentrations were measured after eating a breakfast meal for 3 consecutive days: the first when no insulin was given, the second with a random assignment to either regular insulin or insulin aspart, and the third when the other insulin preparation was administered. Peak insulin concentrations were higher and peak glucose concentrations were lower with both insulins compared with no insulin. Glycemic control as measured by the glucose concentration under the curve above baseline was significantly improved for insulin aspart compared with no insulin. However, regular insulin did not show a significant improvement compared with no insulin administration. In a follow-up study of 27 gestational diabetic women randomized to treatment with insulin aspart versus regular insulin, a greater reduction in the change from baseline average glucose values was seen in those treated with aspart signifying better postprandial glycemic control.19 However, there was a higher number of hypoglycemic episodes (71%) associated with aspart use, but no severe hypoglycemic event requiring assistance of another individual. Treatment with aspart was associated with significantly lower levels of C-peptide compared with regular insulin, reflecting a lower demand on b-cell function. This is likely attributed to the higher peak insulin concentrations that were achieved in this treatment group. Insulin-specific antibody binding was low in both groups (>1.5%). www.clinicalobgyn.com

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The largest evaluation of insulin aspart use in pregnancy was an open-label, randomized, parallel group study of 322 women with type 1 conducted at 63 sites in 18 countries.20 Study entry required a hemoglobin A1c of r8% at pregnancy confirmation. In this study, the mean of the difference between preprandial and postprandial plasma glucoses were lower for those women receiving insulin aspart, despite comparable hemoglobin A1c levels. Although mean total daily insulin doses were similar between groups, the mean daily requirement of prandial insulin was significantly lower in the insulin aspart group. Rates of hypoglycemia were similar between groups. Obstetrical outcomes such as rates of preeclampsia, preterm labor, and cesarean section were similar between groups. In contrast, women treated with insulin aspart reported significantly greater satisfaction with their assigned treatment as measured by the Diabetes Treatment Satisfaction Questionnaire. In a second report of these women, fetal and perinatal outcomes were reported.21

CONGENITAL MALFORMATION

Rates of perinatal mortality were comparable in pregnancies treated with insulin aspart and regular insulin (14 vs. 22/1000 births, respectively). The frequency and type of congenital malformations were similar between groups (4.3% vs. 6.6%), with the majority involving the cardiovascular system. Rates of LGA and neonatal hypoglycemia were also similar.

TRANSPLACENTAL PASSAGE/ IMMUNOGENICITY

In a subset of 95 women enrolled in the randomized trial, analysis of maternal and cord blood insulin antibody levels demonstrated low levels of insulin-specific antibodies in both insulin groups both at baseline and delivery.22 In addition, www.clinicalobgyn.com

insulin aspart was undetectable in all cord blood samples evaluated. Although not as well studied as insulin lispro, aspart use in pregnancy seems to be comparable with regard to transplacental passage, immunogenicity, and clinical efficacy. Reported data on fetal overgrowth, maternal and perinatal outcomes are still limited. It is expected that as clinical experience with insulin aspart increases, the breadth of knowledge will continue to expand.

Insulin Glulisine Insulin glulisine is the newest RAIA approved for clinical use in the United States in 2004. Insulin glulisine is formulated by replacing asparagine at position B3 with lysine and lysine at position B29 with glutamic acid. It has a similar pharmacologic action profile to both insulin lispro and insulin aspart. Insulin glulisine has been studied for use in both types 1 and 2 diabetes. There are currently no clinical studies published addressing the use of insulin glulisine in pregnancy.

LAIAs The LAIAs are most commonly prescribed using a once-daily dosing regimen, most commonly at night. The relatively flat activity profile of glargine, which is essentially peakless, is attractive for women at risk for nocturnal hypoglycemia. These basal insulins are most often used in women with type 1 diabetes. In women with GDM, the nocturnal basal rate of once-daily dosing is often inadequate to counteract the greater insulin resistance and higher insulin requirements during the daytime hours.

Insulin Glargine Insulin glargine, created by adding 2 molecules of arginine to the C-terminal of the b-chain of human insulin and replacing

Insulin Analogues in GDM aspartic acid with glycine in position A21, was the first LAIA approved for clinical use in 2001. These chemical changes lead to a shift in the isoelectric point to a neutral pH which makes the insulin molecule less soluble thereby allowing it to form a depot which allows for slow release. The advantage of such a formulation is a lengthy constant concentration of insulin without a pronounced peak and less hypoglycemia. This also allows for once-daily dosing which may enhance patient acceptance and satisfaction. However, it should be noted that insulin glargine cannot be mixed with other insulin formulations. TRANSPLACENTAL PASSAGE

Results from human placental cotyledon models of uncomplicated term pregnancies have shown that there is no transplacental crossage at maternal therapeutic concentrations of insulin glargine.23 Transport across the placenta was demonstrated at concentrations 1000-fold higher than clinically therapeutic levels, yet there was a significant difference in the rate of disappearance from the maternal compartment compared with the rate of appearance in the fetal compartment. This suggests that the placenta may sequester some amount of insulin glargine at concentrations at this extreme level. CLINICAL EFFICACY

Until 2008, experience with insulin glargine in pregnancy was limited to case reports of 1 to 6 patients each. Although no conclusions can be made due to the small number of women, glycemia was comparable, if not improved with the analogue, with no cases of congenital malformation. Recent studies have primarily evaluated the use of glargine in pregnant women with type 1 diabetes and are limited to retrospective reviews and observational cohort studies. There are no randomized trials comparing

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pregnancy outcomes of women assigned to insulin glargine and NPH insulin. Four studies have evaluated women diagnosed with GDM treated with insulin glargine.24–27 All of these studies evaluate insulin glargine in a mixed population of women with pregestational and GDM. In a retrospective review of 114 pregnant diabetic women, including 30 GDM, there was no difference in gestational age at delivery, birth weight, respiratory distress syndrome, or admission to the NICU in women treated with glargine compared with NPH.26 In this analysis, total dose of basal insulin was less in those women treated with glargine. With regard to maternal outcomes, rates of preeclampsia or cesarean delivery were similar between groups. A larger retrospective review in which 77% of the study population was diagnosed with GDM evaluated the use of insulin glargine on select maternal and neonatal outcomes.27 This analysis reported a mean birth weight of 3142 ± 606 g for the study population, with a 2% incidence of macrosomia in GDM women. In a smaller retrospective review of 112 women treated with glargine compared with NPH, there was no significant difference in maternal complications of preeclampsia, hypoglycemia, or cesarean delivery between groups in the 59 GDM women studied.25 Rate of LGA infants, Apgar scores, neonatal hypoglycemia, and hyperbilirubinemia, as well as NICU admission were also similar between groups. Interestingly, this analysis found fewer macrosomic infants and lower rates of neonatal hyperbilirubinemia in the pregestational cohort treated with glargine. In a prospective observational cohort of 56 pregestational diabetic and 82 GDM women, those with preexisting diabetes were maintained on their preconception basal insulin and those diagnosed with GDM were randomly assigned to either glargine or NPH. In the GDM women, those treated with NPH had higher fasting glucose levels www.clinicalobgyn.com

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at 36 weeks gestation and required higher doses of basal insulin compared with the glargine group. Total lispro dose was similar between groups. Those treated with NPH had higher rates of hypertensive disorders of pregnancy and more frequent hypoglycemia. With regard to neonatal outcomes, jaundice was more common in the NPHtreated group, but no differences were noted in rate of macrosomia or LGA, neonatal hypoglycemia, respiratory distress syndrome, or 5-minute Apgar >7. There has been concern raised about the increased affinity to IGF-1 that is demonstrated by insulin glargine compared with human insulin with a potential to stimulate fetal growth. The data that exists in the current literature from placental cotyledon models23 and the studies published do not demonstrate an increase in the rate of LGA infants or fetal macrosomia. Although a strictly GDM population has not been studied, the risk of fetal overgrowth and macrosomia are not unique to abnormal glucose metabolism of the GDM cohort. Despite a clear benefit for better glycemia and less hypoglycemia in the nonpregnant diabetic women, current studies are limited by small sample size, mixed population of GDM, and pregestational women studied and do not show a consistent clinical benefit for the use of glargine in the pregnant gravida. A randomized controlled trial of insulin glargine and NPH treatment would further elucidate the perinatal outcomes of interest.

diabetic women, insulin detemir has been shown to have more consistent insulin absorption compared with both insulin glargine and NPH insulin.28 Compared with insulin glargine, detemir is similarly peakless but exhibits a slightly shorter duration of action and therefore is dosed every 12 hours in most diabetic individuals. Until recently, there were only 2 case reports of 11 type 1 diabetic women treated with insulin detemir in the preconceptual period and continued throughout the remainder of the pregnancy.29,30 All women were maintained on this insulin due to significant risk of nocturnal hypoglycemia. No adverse maternal effects or neonatal effects were identified. There is one randomized controlled trial comparing the efficacy of insulin detemir with NPH insulin in pregnant women with Type 1 DM.31 In this trial, 152 women were randomized to insulin detemir and 158 were given NPH insulin up to 12 months prior to pregnancy or within the 1st trimester. Hemoglobin A1c value at 36 weeks gestation, the primary outcome, was similar between treatment groups (6.27% detemir versus 6.33% NPH). Although fasting plasma glucose levels at both 24 and 36 weeks were lower in those women treated with insulin detemir, the 8 point self monitored glucose profiles did not differ. Further studies are needed to adequately address efficacy and safety of insulin detemir in pregnancy. No studies have evaluated the use of insulin detemir for the treatment of women with GDM.

Insulin Detemir

Conclusions

Insulin detemir, approved in 2006, is a LAIA that differs from human insulin by the omission of the amino acid threonine in position B30 and attachment of a C14 fatty acid chain to amino acid B29. In contrast to other insulin analogues, insulin detemir has a low affinity for the IGF-1 receptor (approximately 1/10 that of human insulin). In studies of nonpregnant

Insulin lispro and insulin aspart are the analogues most studied in pregnancy. Studies have consistently shown RAIAs to be clinically effective, with insignificant placental transfer and low immunogenicity. Although clinical experience in pregnancy with LAIAs is increasing, significant gaps remain in addressing their clinical use in pregnancy. Further large-scale randomized

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Insulin Analogues in GDM trials of glargine and detemir use in pregnancy are needed. However, the pharmacodynamic profiles of the LAIAs make their use impractical in women with GDM.

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1. McFarland MB, Langer O, Conway DL, et al. Dietary therapy for gestational diabetes: how long is long enough? Obstet Gynecol. 1999;93: 978–982. 2. Jovanovic-Peterson L, Peterson CM, Reed GF, et al. Maternal postprandial glucose levels and infant birth weight: the Diabetes in Early Pregnancy Study. The National Institute of Child Health and Human Development—Diabetes in Early Pregnancy Study. Am J Obstet Gynecol. 1991;164:103–111. 3. Langer O, Mazze R. The relationship between large-for-gestational-age infants and glycemic control in women with gestational diabetes. Am J Obstet Gynecol. 1988;159:1478–1483. 4. Landon MB, Gabbe SG, Piana R, et al. Neonatal morbidity in pregnancy complicated by diabetes mellitus: predictive value of maternal glycemic profiles. Am J Obstet Gynecol. 1987;156:1089–1095. 5. Bhattacharyya A, Brown S, Hughes S, et al. Insulin lispro and regular insulin in pregnancy. QJM. 2001;94:255–260. 6. Jovanovic L, Ilic S, Pettitt DJ, et al. Metabolic and immunologic effects of insulin lispro in gestational diabetes. Diabetes Care. 1999;22:1422–1427. 7. Boskovic R, Feig DS, Derewlany L, et al. Transfer of insulin lispro across the human placenta: in vitro perfusion studies. Diabetes Care. 2003;26: 1390–1394. 8. Holcberg G, Tsadkin-Tamir M, Sapir O, et al. Transfer of insulin lispro across the human placenta. Eur J Obstet Gynecol Reprod Biol. 2004;115:117–118. 9. Garg SK, Frias JP, Anil S, et al. Insulin lispro therapy in pregnancies complicated by type 1 diabetes: glycemic control and maternal and fetal outcomes. Endocr Pract. 2003;9:187–193. 10. Masson EA, Patmore JE, Brash PD, et al. Pregnancy outcome in Type 1 diabetes mellitus treated with insulin lispro (Humalog). Diabet Med. 2003;20:46–50. 11. Persson B, Swahn ML, Hjertberg R, et al. Insulin lispro therapy in pregnancies complicated by type 1 diabetes mellitus. Diabetes Res Clin Pract. 2002;58:115–121. 12. Wyatt JW, Frias JL, Hoyme HE, et al. Congenital anomaly rate in offspring of mothers with diabetes treated with insulin lispro during pregnancy. Diabet Med. 2005;22:803–807. 13. Aydin Y, Berker D, Direktor N, et al. Is insulin lispro safe in pregnant women: Does it cause any

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adverse outcomes on infants or mothers? Diabetes Res Clin Pract. 2008;80:444–448. Cypryk K, Sobczak M, Pertynska-Marczewska M, et al. Pregnancy complications and perinatal outcome in diabetic women treated with Humalog (insulin lispro) or regular human insulin during pregnancy. Med Sci Monit. 2004;10:PI29–PI32. Durnwald CP, Landon MB. A comparison of lispro and regular insulin for the management of type 1 and type 2 diabetes in pregnancy. J Matern Fetal Neonatal Med. 2008;21:309–313. Lapolla A, Dalfra MG, Spezia R, et al. Outcome of pregnancy in type 1 diabetic patients treated with insulin lispro or regular insulin: an Italian experience. Acta Diabetol. 2008;45:61–66. Mecacci F, Carignani L, Cioni R, et al. Maternal metabolic control and perinatal outcome in women with gestational diabetes treated with regular or lispro insulin: comparison with non-diabetic pregnant women. Eur J Obstet Gynecol Reprod Biol. 2003;111:19–24. Pettitt DJ, Ospina P, Kolaczynski JW, et al. Comparison of an insulin analog, insulin aspart, and regular human insulin with no insulin in gestational diabetes mellitus. Diabetes Care. 2003;26:183–186. Pettitt DJ, Ospina P, Howard C, et al. Efficacy, safety and lack of immunogenicity of insulin aspart compared with regular human insulin for women with gestational diabetes mellitus. Diabet Med. 2007;24:1129–1135. Mathiesen ER, Kinsley B, Amiel SA, et al. Maternal glycemic control and hypoglycemia in type 1 diabetic pregnancy: a randomized trial of insulin aspart versus human insulin in 322 pregnant women. Diabetes Care. 2007;30:771–776. Hod M, Damm P, Kaaja R, et al. Fetal and perinatal outcomes in type 1 diabetes pregnancy: a randomized study comparing insulin aspart with human insulin in 322 subjects. Am J Obstet Gynecol. 2008;198:e1–e7. McCance DR, Damm P, Mathiesen ER, et al. Evaluation of insulin antibodies and placental transfer of insulin aspart in pregnant women with type 1 diabetes mellitus. Diabetologia. 2008;51: 2141–2143. Pollex EK, Feig DS, Lubetsky A, et al. Insulin glargine safety in pregnancy: a transplacental transfer study. Diabetes Care. 2010;33:29–33. Negrato CA, Rafacho A, Negrato G, et al. Glargine vs. NPH insulin therapy in pregnancies complicated by diabetes: an observational cohort study. Diabetes Res Clin Pract. 2010;89:46–51. Fang YM, MacKeen D, Egan JF, et al. Insulin glargine compared with neutral protamine hagedorn insulin in the treatment of pregnant diabetics. J Matern Fetal Neonatal Med. 2009;22: 249–253.

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26. Egerman RS, Ramsey RD, Kao LW, et al. Perinatal outcomes in pregnancies managed with antenatal insulin glargine. Am J Perinatol. 2009; 26:591–595. 27. Henderson CE, Machupalli S, Marcano-Vasquez H, et al. A retrospective review of glargine use in pregnancy. J Reprod Med. 2009;54:208–210. 28. Heise T, Nosek L, Ronn BB, et al. Lower withinsubject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes. 2004;53: 1614–1620.

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29. Lapolla A, Di Cianni G, Bruttomesso D, et al. Use of insulin detemir in pregnancy: a report on 10 Type 1 diabetic women. Diabet Med. 2009;26: 1181–1182. 30. Sciacca L, Marotta V, Insalaco F, et al. Use of insulin detemir during pregnancy. Nutr Metab Cardiovasc Dis. 2010;20:e15–e16. 31. Mathiesen ER, Hod M, Ivanisevic M, et al. Maternal efficacy and safety outcomes in a randomized, controlled trial comparing insulin detemir with NPH insulin in 310 pregnant women with type 1 diabetes. Diabetes Care. 2012;35:2012–2117.