Premenopausal and postmenopausal women during the COVID-19 pandemic.

The current global COVID-19 mortality rate is estimated to be around 3.4%; however, it is dependent on age, sex, and comorbidities. Epidemiological evidence shows gender disparities in COVID-19 severity and fatality, with non-menopausal females having milder severity and better outcomes than age-matched males. However, the difference vanishes when comparing postmenopausal women with age-matched men. It has been suggested that, to some extent, this is due to the protective role of female hormones, such as anti-Müllerian hormone and oestradiol (E2), in non-menopausal women. Oestrogens have been hypothesized to be crucial in modulating viral infection and the progression of the disease via an action on immune/inflammatory responses and angiotensin-converting enzyme type 2 expression. Hence, the most likely explanation is that, because the levels of oestrogen in females after menopause decrease, oestrogen no longer offers a beneficial effect as seen in younger females. The COVID-19 pandemic has highlighted the serious negative effects arising from the state of E2 deficiency. Therefore, hormone replacement therapy gains further support as the damaging effect of the decline in ovarian function affects many biological systems, and recently with the COVID-19 pandemic, oestrogen's vital role within the immune system has become quite clear. However, additional clinical investigations regarding hormone replacement therapy are urgently needed to further verify the protective and therapeutic effects of E2 on menopausal women with COVID-19.

Postmenopausal women in gynecological care.

Menopause is one of the most important events in the female reproductive life cycle, being a transition from the reproductive to the nonreproductive stage. It is a milestone that may have a negative influence on quality of life and one that brings in several physiological changes that affect the life of a woman permanently. According to a Polish epidemiological forecast, in 2050 the average female life expectancy will be 87.5, which is 6.4 years longer than today. Thus, the life expectancy of women who will be 60 or older in 2050 will also extend. Therefore, strategies need to be optimized to maintain postreproductive health, in part because of increased longevity. The general gynecologist can expect to see more elderly female patients as the population continues to age. Office management of the gynecologic problems of geriatric women requires sensitivity to the special needs of this group. Nowadays, most women spend more than one-third of their lives after menopause; therefore there is plenty of opportunity for gynecologists to cater to the needs of postmenopausal women. It is in their scope of practice to help postmenopausal women through "healthy aging". In this review we look into screenings, early identification, lifestyle modifications and appropriate intervention that may prevent many chronic conditions that cause morbidity and mortality during the postmenopausal years.

The possible impact of advanced glycation end products on pregnancy outcome in women with diabetes mellitus type 1.

Diabetes mellitus (DM) is a group of metabolic disorders of carbohydrate metabolism in which glucose is underutilized, resulting in hyperglycemia. Reproductive impairment in poorly controlled diabetes mellitus type 1 (T1DM) results from a combined effect of insulin deficiency and hyperglycemia that disrupt the functioning of metabolic signals participating in the regulation of the reproductive system. Good metabolic control as a result of intensive insulin therapy has a great impact on the fertility and childbearing possibilities in the T1DM females. Advanced glycation end products (AGEs) are formed by nonenzymatic modification of proteins, lipids, and nucleic acids by glucose. The formation and accumulation of AGEs are known to progress at an accelerated rate in diabetes. AGEs either act on the pro-inflammatory cell surface receptors called RAGE or bind to the circulating anti-inflammatory sRAGE that prevents activation of cell-surface RAGE by AGEs and other proinflammatory ligands. Pregnancy has been found to induce a significant increase in RAGE protein levels in both myometrium and omental vasculature. This review will focus on the role of AGEs and RAGE in pregnancy complicated by DM type 1 as well as ways to reduce the rate of congenital malformations in the offspring of diabetic type 1 women.

Aging ovary and the role for advanced glycation end products.

OBJECTIVE: The hypothalamic gonadotropin-releasing hormone pulse generator, the pituitary gonadotropes, the ovaries, and the uterus play a crucial role in female fertility. A decline in reproductive performance represents a complex interplay of actions at all levels of the hypothalamic-pituitary-ovarian axis. Recently, in the field of female reproductive aging attention is drawn to the carbonyl stress theory. Advanced glycation end products (AGEs) contribute directly to protein damage, induce a chain of oxidative stress (OS) reactions, and increase inflammatory reactions. Here, we highlight some of the mechanisms underlying glycation damage in the ovary. METHODS: Searches of electronic databases were performed. Articles relevant to possible role of OS, AGEs, and receptor for AGE (RAGE) in aging ovary were summarized in this interpretive literature review. RESULTS: Follicular microenvironment undergoes an increase in OS with aging. Data support the role of OS in ovulatory dysfunction because AGEs are well-recognized mediators of increased OS. RAGE and AGE-modified proteins with activated nuclear factor-kappa B are expressed in human ovarian tissue. It was suggested that accumulation of AGEs products at the level of the ovarian follicle might trigger early ovarian aging or could be responsible for reduced glucose uptake by granulosa cells, potentially altering follicular growth. Moreover, impaired methylglyoxal detoxification causing relevant damage to the ovarian proteome might be one of the mechanisms underlying reproductive aging. CONCLUSIONS: Further investigation of the role for the AGE-RAGE axis in the ovarian follicular environment is needed, and results could relate to assisted reproduction technology outcomes and new measures of ovarian reserve.

2D/3D ultrasonography for endometrial evaluation in a cohort of 118 postmenopausal women with abnormal uterine bleedings.

OBJECTIVES: 2D/3D transvaginal ultrasonography in evaluation of endometrium in postmenopausal women with abnormal uterine bleedings (AUB). MATERIAL AND METHODS: 2D/3D transvaginal ultrasonography (TVU) was performed in 118 menopausal women with AUB. Endometrial volume and thickness, uterine volume and endometrial vascularity were evaluated. Complete histologic evaluation of the endometrium was obtained through dilatation & curettage (D&C) and/or hysteroscopy. Accordingly, patients were divided into 3 groups: controls (no endometrial pathology, n = 49), GI (benign endometrial pathology, n = 37), GII (endometrial carcinoma, n = 32). RESULTS: GII had greater thickness and volume of the endometrium, compared to GI and controls. The presence of arterial vascular flow was identified only in GI and GII (51.35% and 93.75%, respectively). Endometrial volume merged together with uterine volume measurements (TVU-3D) showed a strong, statistical significance between GI and GII, allowing differentiation of begin and malignant endometrial pathologies in postmenopausal women. CONCLUSIONS: In TVU diagnostics of postmenopausal women with AUB the following play the most significant role: 1) endometrial thickness (TVU-2D); 2) endometrial volume (TVU-3D); 3) uterine plus endometrial volume (TVU-3D); 4) vascularization within the endometrium, allowing to differentiate between pathological and normal endometrium (TVU-2/3D). Evaluation of the endometrial vascularity, both in TVU-2D and TVU-3D technique, does not allow for reliable differentiation between benign lesions and endometrial cancer.

Metabolic disorders in menopause.

Metabolic disorders occurring in menopause, including dyslipidemia, disorders of carbohydrate metabolism (impaired glucose tolerance - IGT, type 2 diabetes mellitus - T2DM) or components of metabolic syndrome, constitute risk factors for cardiovascular disease in women. A key role could be played here by hyperinsulinemia, insulin resistance and visceral obesity, all contributing to dyslipidemia, oxidative stress, inflammation, alter coagulation and atherosclerosis observed during the menopausal period. Undiagnosed and untreated, metabolic disorders may adversely affect the length and quality of women's life. Prevention and treatment preceded by early diagnosis should be the main goal for the physicians involved in menopausal care. This article represents a short review of the current knowledge concerning metabolic disorders (e.g. obesity, polycystic ovary syndrome or thyroid diseases) in menopause, including the role of a tailored menopausal hormone therapy (HT). According to current data, HT is not recommend as a preventive strategy for metabolic disorders in menopause. Nevertheless, as part of a comprehensive strategy to prevent chronic diseases after menopause, menopausal hormone therapy, particularly estrogen therapy may be considered (after balancing benefits/risks and excluding women with absolute contraindications to this therapy). Life-style modifications, with moderate physical activity and healthy diet at the forefront, should be still the first choice recommendation for all patients with menopausal metabolic abnormalities.

Advanced glycation end products: A link between metabolic and endothelial dysfunction in polycystic ovary syndrome?

Polycystic ovary syndrome (PCOS), a heterogeneous syndrome of reproductive and metabolic alterations, is associated with increased long-term risk of cardiovascular complications. This phenomenon has been linked to an increase in oxidative stress and inflammatory markers. Advanced glycation end products (AGEs) are pro-inflammatory molecules that trigger a state of intracellular oxidative stress and inflammation after binding to their cell membrane receptors RAGE. The activation of the AGE-RAGE axis has been well known to play a role in atherosclerosis in both men and women. Women with PCOS have systemic chronic inflammatory condition even at the ovarian level as represented by elevated levels of serum/ovarian AGEs and increased expression of the pro-inflammatory RAGE in ovarian tissue. Data also showed the presence of sRAGE in the follicular fluid and its potential protective role against the harmful effect of AGEs on ovarian function. Thus, whether AGE-RAGE axis constitutes a link between metabolic and endothelial dysfunction in women with PCOS is addressed in this review. Additionally, we discuss the role of hormonal changes observed in PCOS and how they are linked with the AGE-RAGE axis in order to better understand the nature of this complex syndrome whose consequences extend well beyond reproduction.

Effect of transdermal hormone therapy on platelet haemostasis in menopausal women.

INTRODUCTION: Despite the undeniably positive effect on the quality of life of menopausal women, menopausal hormone therapy (HT) also has negative side-effects, which include, among others, thromboembolic complications. OBJECTIVE: To assess the effect of a popular type of this therapy - transdermal HT on platelet hemostasis, which plays a significant role in intravascular coagulation. MATERIALS AND METHOD: The study group consisted of 92 postmenopausal women: 1) group G1 (n=30), treated with transdermal HT (17ß-estradiol 50 µg/day plus NETA 170 µg/day); 2) group G2 (n=31), treated with the above transdermal HT and low dosage of acetylsalicylic acid (ASA); 3) control group P (n=31). All the women qualified for the study had two or more risk factors for arterial thrombosis, such as: smoking, hypertension, visceral obesity, hypercholesterolaemia, hypertriglyceridaemia, elevated levels of PAI-1, and increased fibrinogen, increased activity of coagulation factor VII. RESULTS: After three months of therapy, in the G1 group there was a decrease in platelet count (p = 0.004) and a decrease in GP IIb/IIIa - a platelet receptor for fibrinogen (p = 0.022). In the G2 group, no changes in the tested parameters were observed. CONCLUSIONS: 1) Transdermal HT in the form of combined, estrogen-progestogen patches favourably modifies platelets haemostasis, reversing the adverse effects that occur after menopause. 2) The use of low ASA doses as a thromboprophylaxis in short-term transdermal HT is not necessary.

Relationship of Advanced Glycation End Products With Cardiovascular Disease in Menopausal Women.

Cardiovascular disease (CVD) represents the most significant cause of death in postmenopausal women. Advanced glycation end products (AGEs) are formed by nonenzymatic modification of proteins, lipids, and nucleic acids by glucose. This review focuses on the contribution of AGEs and their receptors to the development of CVD in menopause. Advanced glycation end products circulate and activate the proinflammatory endothelial cell surface receptor called RAGE, bind to the extracellular matrix of the cardiovascular system, or bind to the circulating anti-inflammatory soluble form of RAGE (sRAGE). Data emerging from human and animal studies suggest that AGEs and both receptors (RAGE and sRAGE) are implicated in the pathophysiology of CVD. Particular emphasis has been given to the role of AGE-RAGE axis in oxidative stress, inflammation, endothelial cell toxicity, and progression of atherosclerosis in menopause. Data accruing from human and animal studies suggest that RAGE expression level and circulating sRAGE level are associated with estradiol and are correlated with CVD risk factors, such as adiposity, dyslipidemia, insulin resistance, diabetes, and metabolic syndrome. By recognizing the impact of AGEs on atherosclerosis, pharmacological strategies targeting the AGE-RAGE pathway hold therapeutic potential for CVD in menopausal women.

Profile of peripheral blood neutrophil cytokines in diabetes type 1 pregnant women and its correlation with selected parameters in the newborns.

PROBLEM: Interleukin (IL)-12, IL-10, tumor necrosis factor-alpha (TNF-alpha), IL-6 and IL-8 alter as pregnancy progresses, implying continuous immune regulation associated with the maintenance of pregnancy. We aimed to evaluate the peripheral blood neutrophil-derived production of these cytokines in the course of pregnancy complicated by type 1 diabetes. METHOD: of study These parameters were measured in samples from healthy non-pregnant (C), diabetic non-pregnant (D), healthy pregnant (P) and pregnant diabetic (PD) women. RESULTS: Neutrophil-derived secretion of TNF-alpha and IL-12 increased along with progression of pregnancy in PD and P groups. The concentration of IL-10 from lipopolysaccharide (LPS)-stimulated neutrophils increased during the course of uncomplicated pregnancy but decreased in diabetic pregnancy. Concentration of IL-8 decreased with the advancing gestational age in P and PD groups. LPS-stimulated neutrophil-derived IL-6 concentration increased only in PD patients. CONCLUSION: Our results show that diabetes creates pro-inflammatory environment thus potentially influencing the outcome of pregnancy. We conclude that neutrophil-derived cytokine production could contribute to the complications seen in pregnant women with type 1 diabetes.

Evaluation of lectin pathway activity and mannan-binding lectin levels in the course of pregnancy complicated by diabetes type 1, based on the genetic background.

INTRODUCTION: There are numerous indications that either mannan-binding lectin (MBL) deficiency or its excessive activity are associated with adverse pregnancy outcomes. High MBL concentrations and corresponding MBL2 genotypes were shown to be associated with microvascular complications in type 1 diabetes. The aim of this study was to evaluate levels of MBL and MBL-dependent activity of the lectin pathway (LP) of complement in the course of pregnancy in diabetic mothers, based on genetic background. MATERIALS AND METHODS: These parameters were determined in samples from healthy non-pregnant (control), diabetic non-pregnant, healthy pregnant, and pregnant diabetic women. RESULTS: No significant differences in median MBL levels or LP activities were found in any study group compared to the control. However, statistically significant differences in MBL levels were noted during pregnancy between the 1st and 3rd trimesters in both healthy controls and pregnant diabetics. With regard to LP values, similar trends were evident, but statistically significant results were obtained only in the healthy pregnant group. When data analysis was confined to patients carrying the A/A (wild-type) MBL2 genotype, an increase in MBL level during pregnancy (in both healthy and diabetic pregnant women) was still observed. Similarly, LP activity increased during both healthy and diabetic pregnancies, significantly so for the former. CONCLUSIONS: Diabetes, an autoimmune disease, is a serious complication of pregnancy. Therefore, determination of MBL status might be beneficial in identifying type 1 diabetic patients who are at increased risk of developing both vascular complications and poor pregnancy outcomes.

Glycation endproducts, soluble receptor for advanced glycation endproducts and cytokines in diabetic and non-diabetic pregnancies.

PROBLEM: Cytokines, advanced glycation end products (AGEs), and their receptor RAGE have been recently suggested to play a role in human pregnancy. In this study, we sought to determine the alterations of plasma AGEs, soluble RAGE (sRAGE), and proinflammatory cytokines in normal pregnancies and those complicated with type 1 diabetes mellitus. METHOD OF STUDY: These parameters were measured in samples from healthy non-pregnant (C), diabetic non-pregnant (D), healthy pregnant (HP), and pregnant diabetic (DP) women. RESULTS: In the first trimester, DP showed lower sRAGE and higher AGEs compared to HP. In the DP group, significant negative correlations were seen between TNF-alpha and lipopolysaccharide (LPS)-stimulated IotaL-6 in the first trimester and sRAGE in the third trimester. LPS-stimulated IL-12 was positively correlated with levels of AGEs in the third trimester. CONCLUSION: We detected several differences in the levels of AGEs, sRAGE, and proinflammatory cytokines between euglycemic and diabetic pregnancies.

A comparison of the effectiveness, tolerability and safety of high and low carbohydrate diets in women with gestational diabetes.

INTRODUCTION: Nutrition therapy is an integral part of the management of gestational diabetes mellitus (GDM). Most women with GDM are treated by nutritional management alone. The goal of our study was to compare low and high carbohydrate diets in their effectiveness, safety and tolerability in women with GDM. MATERIAL AND METHODS: The study group consisted of 30 Caucasian women newly diagnosed with GDM, with a mean age of 28.7 +/- 3.7 years and pregnancy duration of 29.2 +/- 5.4 weeks. The patients were randomised into two groups: those on a low and those on a high carbohydrate diet (45% vs. 65% respectively of energy supply coming from carbohydrates). The presence of urine ketones was controlled every day. After two weeks daily glucose profiles and compliance with the recommended diets were analysed. RESULTS: Glucose concentration before implementation of the diet regimen did not differ between groups. No changes in fasting blood glucose were noticed in the group that had followed a low carbohydrate diet, although a significant decrease in glucose concentration was observed after breakfast (102 +/- 16 vs. 94 +/- 11 mg/dl), lunch (105 +/- 12 vs. 99 +/- 9 mg/dl) and dinner (112 +/- 16 vs. 103 +/- 13 mg/dl) (p < 0.05). In the high carbohydrate diet group fasting and after-breakfast glucose concentration did not change. A significant decrease in glycaemia was noticed after lunch (106 +/- 15 vs. 96 +/- 7 mg/dl) and dinner (107 +/- 12 vs. 97 +/- 7 mg/dl) (p < 0.05). Ketonuria was not observed in either group. Obstetrical outcomes did not differ between groups. CONCLUSIONS: Both high and low carbohydrate diets are effective and safe. A diet with carbohydrate limitation should be recommended to women who experience the highest glycaemia levels after breakfast.

[Overweight and obesity as common risk factors for gestational diabetes mellitus (GDM), perinatal macrosomy in offspring and type-2 diabetes in mothers]. / Nadwaga i otyltosc--ogniwem laczacym cukrzyce ciazowa, makrosomie urodzeniowa i cukrzyce typu 2.

UNLABELLED: Gestational diabetes mellitus (GDM) affects about 5% of all pregnancies and results in an increased incidence of Caesarean sections, perinatal traumas and neonatal complications. Macrosomy, i.e., an excessive birth-weight is observed in newborns from these pregnancies. In the majority of cases, diabetes regression is observed directly after pregnancy termination, however, in 15-60% of these patients, diabetes mellitus develops in later years of life. The goal of the study was an assessment of the risk factors for GDM development in gestation, perinatal macrosomy in offspring from GDM-affected pregnancies and overt diabetes mellitus in women after GDM. MATERIAL AND METHODS. The study involved 146 women with GDM and 1806 women with normal carbohydrate metabolism during pregnancy, 506 newborns of gestational diabetic mothers and 993 newborns of healthy mothers, as well as 200 women with a history of GDM during the years 1990-1999 (the mean time period after GDM - 3.1 +/- 6.0 years). The recognized risk factors of GDM and perinatal macrosomy were evaluated, together with the incidence of overt diabetes mellitus after GDM-affected pregnancy. RESULTS: An analysis of multifactor logistic regression demonstrated that the independent risk factors for GDM include: BMI 3 25 kg/m2 before pregnancy (OR - 2.38), the history of diabetes in family (OR - 1.67), and the third pr further pregnancy (OR - 1.81) - p < 0.05. In turn, experienced obstetric failures and delivery of child with macrosomy features revealed insignificant - p > 0.05. Perinatal macrosomy correlated with mother's BMI and glycaemia during the 2nd hour of diagnostic test (75 g OGTT). No correlations were observed among mother's age, fasting glycaemia levels and HbA1c in mothers. In the group of GDM-affected women, diabetes mellitus type 2 was diagnosed in 34 (17.0%) patients. The the actual BMI > 25 kg/m2 and glycaemia values in the 2nd hour of diagnostic test in the course of GDM diagnosis (p < 0.05). The risk of diabetes was not enhanced in that group of women by family history of diabetes, the age of GDM onset (< 25 years of life), the week of gestation when GDM was diagnosed (< 25 hbd), and the type of GDM therapy (insulin vs. diet) p > 0.05 CONCLUSIONS: Overweight and obesity are both risk factors of gestational diabetes mellitus, delivery of child with macrosomy features and of overt diabetes mellitus later in life.

[Risks factors for the development of diabetes in women with history of gestational diabetes mellitus]. / Czynniki ryzyka zaburzen gospodarki weglowodanowej u kobiet po przebytej cukrzycy ciezarnych.

UNLABELLED: Women who suffered from impaired carbohydrate metabolism during pregnancy are more likely to develop different types of diabetes later in their lives. The aim of this paper was to study the risk factors for the development of diabetes in group of women with gestational diabetes mellitus (GDM) in anamnesis. MATERIALS AND METHODS: 200 women took part in this study, who had gestational diabetes diagnosed between 1980-1998. All women were divided into 4 groups depending on the type of disorders occurring at the moment of examination: DM1 - women diagnosed with type I diabetes, DM2 - women diagnosed with type 2 diabetes, IGT-women with glucose levels in OGTT, which applied to impaired glucose tolerance (acc. to WHO criteria), NDM - women with no clinical signs of diabetes, with normal result of OGTT. RESULTS: The risk of diabetes development is significantly higher (independently of the clinical type) in women who had had GDM include: high glucose levels at the time of GDM diagnosis, early onset of symptoms - related to weeks of gestation, and the insulin treatment during pregnancy. However multifactor analysis indicates that the only significant risk factors for DM 1 are early onset of diabetes during pregnancy and high glucose levels 2 hours after OGTT during pregnancy (p < 0.05). High levels of glucose 2 hours after OGTT and high Body Mass Index (BMI) turned out to be the independent risk factors of diabetes type 2 (p < 0.05). CONCLUSIONS: Knowledge of risk factors allows to recognize a diabetes high risk group among women who suffered from diabetes during pregnancy.

Advanced glycation end products upregulate angiogenic and pro-inflammatory cytokine production in human monocyte/macrophages.

Glucose can react non-enzymatically with amino groups of, for example, proteins, to yield derivatives termed advanced glycation end products (AGE), which contribute to many chronic progressive diseases associated with microvascular complications. The study aimed to determine the effect of AGE-modified albumin on THP-1 cells and human monocyte-derived macrophages. Bovine serum albumin (BSA) or human serum albumin (HSA), modified by glucose-derived AGE, was prepared by incubation with glucose for differing periods of time. Alternatively, BSA was incubated with sodium cyanoborohydride and glyoxylic acid to produce N(epsilon)-(carboxymethyl)lysine-modified BSA (CML-BSA). Stimulation for 24h of THP-1 cells with BSA, incubated for 6-8 weeks with glucose, induced significant VEGF release. Human monocyte-derived macrophages stimulated with extensively glycated HSA also showed significant VEGF release, as well as upregulation of IL-8 production, incubation for 6h with extensively glycated HSA increased release of TNFalpha and expression of tissue factor. Finally, addition of CML-BSA resulted in significant induction of TNFalpha and VEGF release. We demonstrate that a range of different methods of glycation of BSA and HSA, including CML-BSA, resulted in the induction of VEGF, TNFalpha, IL-8 and expression of tissue factor, according to length of stimulation and different glycation products used, suggesting that AGE-induced activation of macrophages may contribute to vascular complications by regulation of angiogenic, inflammatory and pro-coagulant processes.

Pregnancy complications and perinatal outcome in diabetic women treated with Humalog (insulin lispro) or regular human insulin during pregnancy.

BACKGROUND: Pregnancy outcome in diabetic women is strictly related to glycemic control during pregnancy. The aim of our study was to compare pregnancy outcome between patients subjected to intensive insulin therapy using regular human insulin and those treated with insulin lispro (Humalog). MATERIAL/METHODS: Group A (n=25) was treated with Humalog, and the control group B (n=46) with regular human insulin. Mean age, duration of diabetes, presence of chronic diabetic complications (according to the White classification) parity, and BMI did not differ between groups. RESULTS: The mean HbA1c concentrations in groups A and B were respectively: 7.8+/-1.4% vs. 7.5+/-1.5% in the first trimester, 6.4+/-0.8% vs. 6.5+/-1.6% in the second, and 6.7+/-0.7% vs. 6.3+/-1.2% in the third (no significant differences). The duration of pregnancy was 36.4+/-3.9 weeks in group A and 37.1+/-1.9 weeks in group B, while the mean neonatal birth weight was 3467+/-790 and 3367+/-666 g, respectively. Neither the frequency of preterm labor and cesarean section nor the frequency of fetal macrosomia and hypoglycemia differed between groups. There was only one malformed infant in the human insulin-treated group, and no statistical difference in the rate of spontaneous abortion between groups. Also, there were no differences in the frequencies of occurrence of hypertension (essential and pregnancy induced) and urinary tract infections. CONCLUSIONS: The course of pregnancy and perinatal outcome is comparable in intensively treated diabetic women regardless of the short-acting insulin used. Humalog appears to be a safe alternative to human insulin in the treatment of diabetes during pregnancy.