Commentary from the Italian Association of Medical Diabetologists (AMD) and Italian Society of Diabetology (SID) Interassociative Diabetes and Pregnancy Study Group on the screening and diagnostic methods for gestational diabetes: An open debate.

The current board of the interassociative Italian association of medical diabetologists (AMD)/Italian society of diabetology (SID) Diabetes and Pregnancy Italian Study Group commented about two recent papers published in the New England Journal of Medicine that investigated the screening and diagnostic methods for gestational diabetes mellitus (GDM). It is well recognized that effective screening and accurate, early diagnosis of GDM contributes to better management of these women in order to reduce adverse maternal and fetal/neonatal outcomes. However, there is worldwide controversy concerning which screening (selective or universal; one step or two steps) and which diagnostic criteria (glucose thresholds) are appropriate. The main findings of these papers are discussed along with their implications for the management of pregnant women.

A preliminary study on human placental tissue impaired by gestational diabetes: a comparison of gel-based versus gel-free proteomics approaches.

Gestational diabetes (GDM) is the most common complication of pregnancy and it is associated with maternal and fetal short- and long-term consequences. GDM modifies placental structure and function, but many of the underlying mechanisms are still unclear. The aim of this study is to develop and compare two different methods, based respectively on gel-based and gel-free proteomics, in order to investigate the placental proteome in the absence or in the presence of GDM and to identify, through a comparative approach, possible changes in protein expression due to the GDM condition. Placenta homogenates obtained by pooling six control samples and six samples from GDM pregnant women were analyzed by two-dimensional (2D) electrophoresis coupled with mass spectrometry [nano-liquid chromatography (nano-LC) tandem mass spectrometry (MS/MS) and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS)] and by a label-free mass spectrometry method based on LC-MS(E). The gel-based approach highlights 13 over-expressed proteins and 16 under-expressed proteins, while the label-free method shows the over- expression of 10 proteins and the under-expression of nine proteins. As regards 2D gel electrophoresis, a comparison between two different protein identification methods, based respectively on nLC-electrospray ionization-MS/MS and MALDI-MS/MS, was performed taking into consideration the sequence coverage, the MASCOT score and the exponentially modified protein abundance index. The analysis of the complex proteome through an integrated strategy revealed that the quantitative gel-free and label-free MS approach might be suitable to identify candidate markers of GDM.

Lipid profile in women of different ethnicity with gestational diabetes: Relationship with fetal growth.

AIMS/INTRODUCTION: Pregnancy complicated by gestational diabetes mellitus (GDM) is characterized by excessive insulin resistance that impairs the metabolism of glucose and lipids. the aim of the study was to examine lipid profiles during pregnancy of women with GDM, and its impact on fetal growth in a multiethnic population. MATERIALS AND METHODS: The study included 322 pregnant women of different ethnicity with GDM attending a clinical unit specializing in metabolic diseases. RESULTS: The area under the curve for the 75-g oral glucose tolerance test and glycated hemoglobin were significantly different among all groups. At the time of being diagnosed with GDM, Asian and African mothers had significantly lower levels of total and low-density liprotein cholesterol than European mothers (P < 0.001). The trend for high-density liprotein cholesterol was similar. Triglycerides levels in the Asian group (193.6 ± 65.5 mg/dL) were higher than in the African group (133.2 ± 49.6 mg/dL, P < 0.001), whereas the European group presented intermediate values (175.8 ± 58.8 mg/dL), which differed significantly only versus the African group (P < 0.001). Pre-partum lipid profiles showed a trend quite similar to that observed at diagnosis. The newborn's birthweight was significantly different, with that of African women (3,437 ± 503 g) being the highest, followed by that of European women (3,294 ± 455 g) and of Asian women (3,006 ± 513 g). The rates of macrosomia showed a trend with higher values in the African group (13.5%), followed by the European group (5.7%, P = 0.1162), whereas that of the Asian group was zero (P = 0.0023 vs African). CONCLUSIONS: Our data show that lipid profiles in women with GDM differ by ethnicity. The impact of lipid profile on fetal growth is limited and uninfluenced by ethnicity.

Pregnancy after Bariatric Surgery: Nutrition Recommendations and Glucose Homeostasis: A Point of View on Unresolved Questions.

Obesity is increasing in all age groups and, consequently, its incidence has also risen in women of childbearing age. In Europe, the prevalence of maternal obesity varies from 7 to 25%. Maternal obesity is associated with short- and long-term adverse outcomes for both mother and child, and it is necessary to reduce weight before gestation to improve maternal and fetal outcomes. Bariatric surgery is an important treatment option for people with severe obesity. The number of surgeries performed is increasing worldwide, even in women of reproductive age, because improving fertility is a motivating factor. Nutritional intake after bariatric surgery is dependent on type of surgery, presence of symptoms, such as pain and nausea, and complications. There is also a risk of malnutrition after bariatric surgery. In particular, during pregnancy following bariatric surgery, there is a risk of protein and calorie malnutrition and micronutrient deficiencies due to increased maternal and fetal demand and possibly due to reduction of food intake (nausea, vomiting). As such, it is necessary to monitor and manage nutrition in pregnancy following bariatric surgery with a multidisciplinary team to avoid any deficiencies in each trimester and to ensure the well-being of the mother and fetus.

Anti-diabetic combination therapy with pioglitazone or glimepiride added to metformin on the AGE-RAGE axis: a randomized prospective study.

Introduction: The ratio between advanced glycation end products (AGEs) and soluble form of receptor (s-RAGE) has been proposed as a risk marker for renal and cardiovascular diseases. The aim of this study was to evaluate in the diabetes condition the influence of two different oral anti-diabetic treatments on the AGE/s-RAGE ratio, during a 5-year observation period. Methods: Seventy-three patients with type 2 diabetes mellitus were randomly assigned to a drug therapy with pioglitazone or glimepiride, combined to metformin. Each subject was evaluated at baseline and after 5 years of treatment. Results: In both groups s-RAGE levels did not significantly vary, while the levels of AGE and AGE/s-RAGE were both significantly reduced, basal compared to 5-year values. Within pioglitazone group, as well within glimepiride group, significant variations (Δ, as difference between 5 years of treatment minus basal) were observed for AGE (Δ= -21.1±13.4 µg/ml, P<0.001 for pioglitazone; Δ= -14.4±11.4 µg/ml, P<0.001 for glimepiride) and in AGE/s-RAGE (Δ= -0.037±0.022 µg/pg, P<0.001 for pioglitazone; Δ= -0.024±0.020µg/pg, P<0.001 for glimepiride), suggesting an average decrease of the parameters by more than 50% in both treatments. Pioglitazone was more effective than glimepiride in reducing AGE/s-RAGE ratio after 5 years of therapy. Conclusion: These data can help to explain the benefits of oral anti-diabetic therapy in relation to the reduction of cardiovascular risk, as suggested by variations in AGE/s-RAGE ratio as biochemical marker of endothelial function; in particular, treatment with pioglitazone seems to offer greater long-term benefit on AGE-RAGE axis.

Position paper of the Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), and the Italian Study Group of Diabetes in pregnancy: Metformin use in pregnancy.

OBJECTIVE: This document purpose is to create an evidence-based position statement on the role of metformin therapy in pregnancy complicated by obesity, gestational diabetes (GDM), type 2 diabetes mellitus (T2DM), polycystic ovary syndrome (PCOS) and in women undergoing assisted reproductive technology (ART). METHODS: A comprehensive review of international diabetes guidelines and a search of medical literature was performed to identify studies presenting data on the use of metformin in pregnancy. The document was approved by the councils of the two scientific societies. RESULTS: In condition affecting the fertility, as PCOS, metformin use in pre-conception or early in pregnancy may be beneficial for clinical pregnancy, even in ART treatment, and in obese-PCOS women may reduce preterm delivery. In obese women, even in the presence of GDM or T2DM, metformin use in pregnancy is associated with a lower gestational weight gain. In pregnancy complicated by diabetes (GDM or T2DM), metformin improves maternal glycemic control and may reduce insulin dose. Neonatal and infant outcomes related to metformin exposure in utero are lacking. Metformin use in women with GDM or T2DM is associated with lower birth weight. However, an increased tendency to overweight-obesity has been observed in children, later in life. CONCLUSIONS: Metformin may represent a therapeutic option in selected women with obesity, PCOS, GDM, T2DM, and in women undergoing ART. However, more research is required specifically on the long-term effects of in utero exposition to metformin.

Weight gain during pregnancy: A narrative review on the recent evidences.

Gestational weight gain is necessary for the normal fetus development, in fact a series of studies have evidenced that both low and excessive gestational weight gain is associated with negative fetal-neonatal outcomes. So, evidences on the optimal gestational weight gain across the ranges of the pre-pregnancy maternal body mass index are necessary. In this context, while for normal weight and underweight the recommendations of IOM are clearly stated and supported by well designed and conducted clinical studies, those for the obese pregnant women are even today debated. Pre-pregnancy obesity is associated with high risk to develop hypertension, gestational diabetes, cesarean section and high birth weight. The Institute of Medicine guidelines, in 2009, recommended that women with obesity gain 11-20 lb at a rate of 0.5 lb/week during the second and third trimesters of pregnancy. Successively, taking into account a series of meta-analysis, the American College of Obstetricians and Gynecologists emphasized that the IOM weight gain targets for obese pregnant women are too high. However the high risk to have babies small for gestational age, related to a low weight gain or a losing of weight during pregnancy, has also been demonstrated. More recent studies have taken into consideration the maternal and fetal outcomes of obese pregnant women with different obesity class (I,II,III) and different weight gain during pregnancy. The analysis of these studies, discussed in this narrative review, show that the appropriate gestational weight gain should be personalized considering the three obesity class; furthermore both an upper and lower limit of gestational weight gain should be reconsidered in order to prevent the negative maternal and fetal outcomes in these women.

Can the First Fasting Plasma Glucose Test in Pregnancy Predict Subsequent Gestational Complications?

Objective: To determine the best cut-off level of pregnant women's first fasting plasma glucose (FFPG) test results for the prediction of subsequent onset of gestational diabetes mellitus (GDM) and to examine the association between FFPG and maternal and neonatal outcomes in a large Caucasian population. Methods: 1437 medical records of women with singleton pregnancies followed up between 2015 and 2018 were retrospectively analyzed. Data on FFPG tested in the first trimester and 75 g oral glucose tolerance test (OGTT) findings performed according to IADPSG criteria and Italian guidelines were collected and evaluated. The women's clinical and metabolic characteristics (age, prepregnancy body mass index (BMI), previous pregnancies complicated by GDM, timing of delivery, and gestational hypertension) were also recorded. The fetal variables considered were being large for gestational age (LGA) or small for gestational age (SGA), macrosomia, and hypoglycemia. Results: Among the 1437 pregnant women studied, 684 had a normal glucose tolerance (NGT) and 753 developed GDM. In a univariate analysis FFPG ≥92 mg/dl predicts the risk of GDM with an OR = 2.36 (95% CI 1.930-3.186; p < 0.001). In multivariate analysis, after adjusting for principal risk factors of GDM (BMI, previous GDM, age >35 years, family history of diabetes) FFPG ≥92 mg/dl was associated with the risk of GDM (OR = 1.92; 95% CI 1.488-2.492; p < 0.001). In univariate analysis, FFPG ≥92 mg/dl predict the risk of insulin therapy in GDM women with a OR = 1.88 (95% CI 1.230-2.066; p < 0.001). As regards LGA, in a multivariate analysis, after adjusting for BMI, FFPG ≥92 mg/dl was associated with the risk of LGA only in NGT women (OR = 2.34; 95% CI 1.173-4.574; p=0.014), but not in GDM women. FFPG was not associated with other maternal or neonatal outcomes. Conclusions: FFPG ≥92 mg/dl is related to GDM diagnosis and to the need of insulin therapy if GDM is diagnosed. An early diagnosis and a prompt start of insulin therapy are essential to prevent maternal and fetal complications.

Knowledge, attitude, and practice of the 2009 Institute of Medicine (IOM) recommendations on the nutritional management of diabetes in pregnancy: an online national survey.

AIMS: As recommended by the Institute of Medicine (IOM), health practitioners should encourage a healthy nutrition and adequate weight gain during pregnancy in order to ensure favorable pregnancy and fetal outcomes, and to prevent diseases later in life for both mother and child. The purpose of this online survey was to determine the knowledge, attitude, and practice of the 2009 IOM recommendations among healthcare professionals managing nutritional therapy in pregnancies complicated by diabetes in Italy. METHODS: A cross-sectional survey was conducted by using an online self-administered questionnaire undertaken between October and December 2021. RESULTS: Of the 220 participants 89% were diabetologists/endocrinologists/internal medicine specialists and 11% dietitians/nutritionists. The survey found that the 53% of respondents provide a personalized diet to pregnant women with diabetes, while 32% a standard diet plan and only 15% healthy dietary advice. The 69% of the participants investigated for appropriate gestational weight gain, mainly based on pre-pregnancy BMI (96%), gestational weight gain (GWG) at first prenatal visit (80%) and presence of twin pregnancy (58%). Maternal weight gain was evaluated at each regularly scheduled prenatal visit and compared with IOM recommendations for the 87% of healthcare professionals. Diet plan was periodically re-evaluated and/or modified (90% of participants), based on inadequate maternal weight gain and/or fetal growth abnormalities (78%), trimester transition (53%), changes in physical activity and/or a "feel hungry" (50%). CONCLUSIONS: This survey reported the knowledge and attitude of IOM guidelines and the nutritional knowledge and practice of Italian professionals on the nutritional management of diabetes in pregnancy. The application of these recommendations seemed more feasible in clinics/team dedicated to "Diabetes in Pregnancy".

Adherence to a follow-up program after gestational diabetes.

AIM: The aim of this study was to examine attendance for early postpartum follow-up among women with gestational diabetes mellitus (GDM), and to identify factors that influenced their likelihood of attending. METHODS: One thousand eight hundred and nineteen women with GDM were retrospectively analyzed. During pregnancy, the following data were collected: age, family history of diabetes, ethnicity, prepregnancy BMI, fasting plasma glucose, glycated hemoglobin, gestational week of GDM diagnosis, timing and mode of delivery, newborn's birth weight and length. Glycemia and insulinemia during OGTT, lipid profile and postpartum BMI were assessed at follow-up. Based on the OGTT, women were classified as having normal glucose tolerance (NGT) or abnormal glucose tolerance (AGT), which included impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG + IGT, and DM2. Factors predicting postpartum attendance for follow-up and onset of AGT were considered. RESULTS: Of the 889 (48.9%) who attended the scheduled postpartum OGTT, 741 (83.4%) had NGT, while 148 (16.6%) had AGT (IFG 6.7%, IGT 7.7%, IFG + IGT 0.8%, DM2 1.5%). The predictors of adherence to follow-up were: not belonging to an immigrant group; family history of DM2; and insulin therapy in pregnancy. The same factors were also predictive of AGT. Our data suggest a role of ethnicity in both attendance for postpartum follow-up and its outcome. CONCLUSION: Despite efforts to provide care for women with GDM, postpartum screening rates are still low among Italian women, and especially among immigrants. Hence, the need to improve these patients' awareness of the severe risk of developing diabetes after pregnancy, concentrating efforts especially on women belonging to the most at risk ethnic groups.

Genetics and Epigenetics: New Insight on Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is the most common metabolic complication of pregnancy, with a prevalence that has increased significantly in the last decade, coming to affect 12-18% of all pregnancies. GDM is believed to be the result of a combination of genetic, epigenetic and environmental factors. Following the identification of susceptibility genes for type 2 diabetes by means of genome-wide association studies, an association has also been demonstrated between some type 2 diabetes susceptibility genes and GDM, suggesting a partial similarity of the genetic architecture behind the two forms of diabetes. More recent genome-wide association studies, focusing on maternal metabolism during pregnancy, have demonstrated an overlap in the genes associated with metabolic traits in gravid and non-gravid populations, as well as in genes apparently unique to pregnancy. Epigenetic changes-such as DNA methylation, histone modifications and microRNA gene silencing-have also been identified in GDM patients. Metabolomics has been used to profile the metabolic state of women during pregnancy, based on the measurement of numerous low-molecular-weight metabolites. Measuring amino acids and conventional metabolites has revealed changes in pregnant women with a higher insulin resistance and high blood glucose levels that resemble the changes seen in non-gravid, insulin-resistant populations. This would suggest similarities in the metabolic profiles typical of insulin resistance and hyperglycemia whether individuals are pregnant or not. Future studies combining data obtained using multiple technologies will enable an integrated systems biology approach to maternal metabolism during a pregnancy complicated by GDM. This review highlights the recent knowledge on the impact of genetics and epigenetics in the pathophysiology of GDM and the maternal and fetal complications associated with this pathology condition.

Celiac Disease and Pregnancy Outcomes in Patients with Gestational Diabetes Mellitus.

AIM: Gestational diabetes mellitus (GDM) and celiac disease, if not diagnosed and properly treated, are associated with adverse outcomes of pregnancy. The aim of our study was to examine pregnancies complicated by GDM in celiac and nonceliac women in terms of their metabolic parameters and maternal and fetal outcomes. METHODS: The study involved 60 women with GDM, 20 with and 40 without celiac disease. Maternal clinical and metabolic parameters (glucose and insulin levels in the oral glucose tolerance test (OGTT), fasting plasma glucose, HbA1c, lipid profile, prepregnancy BMI, gestational weight gain, and chronic diseases), pregnancy outcomes (gestational hypertension, pre-eclampsia, eclampsia, time, and mode of delivery), and fetal parameters (weight and length at birth, and neonatal complications) were recorded. RESULTS: The two groups did not differ significantly in maternal parameters other than blood glucose levels at 120' in the diagnostic OGTT (141.2 ± 35.2 vs 161.2 ± 35.4, mg/dl, p=0.047), prepartum cLDL (127.2 ± 43.5 vs 179.6 ± 31.7 mg/dl, p ≤ 0.001), and total cholesterol (229.0 ± 45.9 vs 292.5 ± 42.1 mg/dl, p ≤ 0.001), which were significantly lower in celiac women than in nonceliac controls. Children born from celiac women had a significantly higher birth weight (3458.1 ± 409.8 vs 3209.0 ± 432.7 g, p=0.044) and ponderal index (2.89 ± 0.32 vs 2.66 ± 0.25 g/cm3, p=0.006) and were more likely to be large for gestational age (27.8% vs 2.5%, p=0.012). Analyzing the composition of the celiac and nonceliac women's diet showed that, for the same amount of kilocalories, the gluten-free diet was associated with a slight increase in the amount of carbohydrates (49.75% vs 48.54%) and a reduction in the amount of protein (21.10% vs 23.31%) and especially of fiber (9.84% vs 12.71%). CONCLUSIONS: Celiac women with GDM have much the same pregnancy outcomes as nonceliac women with GDM, except for fetal overgrowth. Gluten-free food, being richer in carbohydrates and less rich in fiber and protein, could have a role in fetal growth in celiac women.

Role of fructosamine-3-kinase in protecting against the onset of microvascular and macrovascular complications in patients with T2DM.

INTRODUCTION: Microangiopathic and macroangiopathic complications are the main cause of morbidity and mortality in the diabetic population. Numerous publications have highlighted the role of glycation in the onset of complications of diabetes. In this context, the detection of fructosamine-3-kinase (FN3K)-an enzyme capable of counteracting the effect of hyperglycemia by intervening in protein glycation-has attracted great interest. Several studies have linked FN3K genetic variability to its enzymatic activity and glycated hemoglobin (HbA1c) levels. Here, we investigated the role of FN3K polymorphisms in the development of microvascular and macrovascular complications of diabetes. RESEARCH DESIGN AND METHODS: The anthropometric and biochemical parameters, and any medical history of microangiopathic and macroangiopathic complications, were documented in a sample of 80 subjects with type 2 diabetes. All subjects were screened for FN3K gene and analyzed for the combination of three polymorphisms known to be associated with its enzymatic activity (rs3859206 and rs2256339 in the promoter region and rs1056534 in exon 6). RESULTS: The combination of allelic variants of FN3K polymorphisms resulted in 13 distinct genotypic variants within the cohort. Comparison between genotypes showed no significant differences in terms of demographic, anthropometric and biochemical parameters, risk markers and long-term complications, except for a higher age and vitamin E levels associated with the genotype presenting GG at position -385, TT at position -232, and CC at c.900 A. Evaluating the microangiopathic and macroangiopathic complications as a whole, we found that they appeared significantly less present in this genotype compared with all other genotypes (p=0.0306). CONCLUSIONS: The group of patients carrying the favorable allele for the three polymorphisms of the FN3K gene revealed less severe microangiopathy and macroangiopathy, suggesting a protective role of this genotype against the onset of the complications of diabetes.

Is the placental proteome impaired in well-controlled gestational diabetes?

In pregnancy complicated by gestational diabetes mellitus (GDM), the human placenta shows several pathological functional and structural changes, but the extent to which maternal glycemic control contributes to placental abnormalities remains unclear. The aim of this study was to profile and compare the proteome of placentas from healthy pregnant women and those with GDM, to investigate the placenta-specific protein composition and possible changes of its function in presence of GDM. Quantitative proteomic analysis, based on LC-MSE approach, revealed that higher (approximately 15% increase) levels of galectin 1 and collagen alpha-1 XIV chain (although the difference regarding the latter was at the limit of significance) were present in GDM samples, while heat shock 70 kDa protein 1A/1B was less abundant in GDM placental tissue. These data seem to indicate that GDM, when well controlled, did not markedly affect the placental proteome.

Long-term effect of pioglitazone vs glimepiride on lipoprotein oxidation in patients with type 2 diabetes: a prospective randomized study.

AIMS: Type 2 diabetes (DM2) is associated to oxidative modifications of high-density lipoproteins (HDL), which can interfere with their function. Pioglitazone has proved effective in raising HDL cholesterol (HDL-C) and lowering small dense low-density lipoprotein (LDL), but no clinical studies have examined its effect on lipoprotein oxidation in patients with DM2. METHODS: We assessed the effect of pioglitazone vs glimepiride after 1 year on HDL oxidation, expressed as relative abundance of peptides containing Met112O in ApoA-I (oxApoA-I) estimated by mass spectrometry (MALDI/TOF/TOF), in 95 patients with DM2. The oxLDL and AGE were quantified by ELISA. RESULTS: Patients receiving pioglitazone showed a significant increase in the concentration of ApoA-I (Δ = 7.2 ± 14.8 mg/dL, p < 0.02) and a reduction in oxApoA-I (Δ = - 1.0 ± 2.6%, p < 0.02); this reduction was not significantly different from glimepiride. oxLDL showed a slight, but not significant increase in both treatment groups. Regression analysis showed a correlation between ΔoxApoA-I and ΔAGE (r = 0.30; p = 0.007) in all patients, while both of these parameters were unrelated to changes in HbA1c, HDL-C, duration of illness, or use of statins. CONCLUSIONS: Long-term treatment with pioglitazone was effective in reducing the oxidation of HDL, but not LDL in patients with DM2, while glimepiride didn't. This finding seems to be associated to the change of glyco-oxidation status, not to any improvement in glycemic control or lipid profile. TRIAL REGISTRATION: NCT00700856, ClinicalTrials.gov Registered June 18, 2008.

Clinical and biochemical approach to predicting post-pregnancy metabolic decompensation.

The prevalence of gestational diabetes in the developed world is increased and parallels that of obesity. Apart from the maternal and fetal complications occurring during pregnancy, GDM is characterized by a high subsequent risk of type 2 diabetes, metabolic syndrome, and cardiovascular disease. In this paper, we outline the different factors to consider in assessing the future risk of diabetes developing in women with a history of GDM. Looking at the modifiable risk factors, it is worth noting that promoting a healthy diet and lifestyle before (physical activity), during and after pregnancy (breast feeding) in women of fertile age are fundamental to the success of efforts to reduce the burden of diabetes in these young people.

Ketoacidosis in diabetic pregnancy.

Diabetic ketoacidosis (DKA) is a serious medical and obstetrical emergency previously considered typical of type 1 diabetes but now reported also in type 2 and GDM patients. Although it is a fairly rare condition, DKA in pregnancy can compromise both fetus and mother. Metabolic changes occurring during pregnancy predispose to DKA in fact it can develop even in setting of normoglycemia. This article will provide the reader with information regarding the pathophysiology underlying DKA, in particular euglycemic DKA, and will provide information regarding all possible effects of ketones on the fetus.

Diabetic pregnancy outcomes in mothers treated with basal insulin lispro protamine suspension or NPH insulin: a multicenter retrospective Italian study.

OBJECTIVE: The aim of this study was to study the efficacy and safety of long-acting insulin analog insulin lispro protamine suspension (ILPS) in diabetic pregnant women. METHODS: In a multicenter observational retrospective study, we evaluated pregnancy outcome in 119 women affected by type 1 diabetes and 814 with gestational diabetes (GDM) treated during pregnancy with ILPS, compared with a control group treated with neutral protamine hagedorn (NPH) insulin. RESULTS: Among type 1 diabetic patients, fasting blood glucose at the end of pregnancy was significantly lower in ILPS-treated than in NPH-treated patients. HbA1c levels across pregnancy did not differ between groups. Caesarean section and preterm delivery rates were significantly lower in the ILPS-women. Fetal outcomes were similar in the ILPS and NPH groups. Among GDM women, fasting blood glucose at the end of pregnancy was significantly lower in ILPS-treated than in NPH-treated patients. Duration of gestation was significantly longer, caesarian section and preterm delivery rates were lower in the ILPS-treated group. In addition, there were significantly fewer babies with an excessive ponderal index or neonatal hypoglycemic episodes in the ILPS group than in the NPH group. CONCLUSIONS: Association of ILPS with rapid-acting analogs in pregnancy is safe in terms of maternal and fetal outcomes.