Manifest diabetes mellitus (MDM) was identified as an independent carbohydrate metabolism disorder during pregnancy in the report of the International Association of Diabetes and Pregnancy Study Groups (IADPSG), which aims to improve the quality of medical help for pregnant women with diabetes [1]. MDM is not identical to gestational diabetes mellitus (GDM). GDM is a disease characterized by hyperglycemia that was first revealed during pregnancy but that does not correspond to the criteria of “manifest” diabetes mellitus. A group of experts expressed concern about an ongoing epidemic of obesity, which leads to an increase in the rate of cases of undiagnosed diabetes mellitus type 2 (DM2) in young women [2–4].

According to the WHO, in 2014, there were 38.9 million pregnant women with excessive weight worldwide; 14.6 million of them had obesity. A report of FIGO for 2018 presented the data on 42 million pregnant women [5][6].

Metabolic changes during pregnancy are associated with growing insulin resistance, which develops because of the appearance of a new organ (placenta). The placenta is an endocrine organ, which releases some protein and steroid hormones into the blood (chorionic gonadotropin hormone, placental lactogenic hormone, progesterone, and estrogens). The hormonal function of the placenta provides the basis for the formation of insulin resistance during pregnancy [7][8].

It is believed that MDM during pregnancy is associated with a significant risk of unfavorable perinatal outcomes. Thus, it has been concluded that it is necessary to detect women with undiagnosed carbohydrate metabolism before pregnancy that can onset with a higher degree of hyperglycemia and associated metabolic disorders. All IADPSG experts agreed that MDM diagnostics should be performed during the first prenatal visit. The diagnostics can be performed using any certified laboratory method: fasting plasma glucose test, glucose tolerance test, and HbA1c test [9].

Timely diagnostics of MDM and initiation of insulin therapy target to reduce the rate of perinatal complications (miscarriage, preeclampsia, preterm delivery, abdominal delivery, neonatal morbidity (birth defects, macrosomia, and diabetic fetopathy)) [10][11].

One of the serious grounds for the early detection of MDM is the risk of the development of diabetic ketoacidosis (DKA). Untimely diagnosed MDM is a reason for the development of DKA during pregnancy in 30% of cases and can lead to the death of not only the newborn but also the mother. The peculiarity of the DKA course in pregnant women with various forms of diabetes mellitus is the fast (several hours) development of metabolic disorders associated with moderate hyperglycemia. Hyperglycemia > 11.1 mmol/L, ketone levels in blood >3.0 mmol/L (β-hydroxybutyric acid), bicarbonate levels < 15.0 mmol/L, and/or blood pH < 7.3 are the diagnostic criteria for DKA during pregnancy.

The negative influence of DKA on the fetus is associated with severe dehydration of the mother during acidosis, which can lead to a reduction of uteroplacental blood flow and fetus hypoxia. The rate of antenatal fetal death in women with DKA varies between 9% and 36%. Women with DKA manifestations should receive medical help within several hours in the conditions of specialized inpatient facilities from a team of specialists that includes an anesthesiologist-reanimatologist, an endocrinologist, and an obstetrician-gynecologist [12–14].

The study aimed to analyze the peculiarities of diagnostics, course, and pregnancy outcomes in women with MDM.

A retrospective analysis of 19 delivery medical records of women with MDM and 500 women with GDM was performed. The average age of pregnant women with MDM was 33.4±4.8 years old, and women with GDM – 28.7±4.9 years old. In the group of women with MDM, body mass index (BMI) was 28.2±8.6 kg/m², and in the group of women with GDM – 30.5 kg/m². All patients were diagnosed with carbohydrate metabolism disorders based on the results of the fasting glucose test as the first group of screening (6/7 to 24 weeks of pregnancy) and oral glucose tolerance test. Stage I includes the first blood probe of fasting venous blood. Stage II includes consumption of glucose for 5 minutes (75 g of dry (anhydrite or anhydrous) glucose diluted in 250–300 ml of warm (37–40 °C) drinking still (or distilled) water. Stage III includes a venous blood probe for glucose one and two hours after glucose loading.

All patients in groups with MDM and GDM were recommended to change their lifestyle (rational diet therapy and physical activity) according to the clinical federal recommendations [9]. The caloric content of food was calculated according to body weight. In patients with BMI 18–24.9 kg/m², daily calorie maintenance was 30 kcal/kg of actual weight. In patients with BMI 25–29.9 kg/m² – 25 kcal/kg, in patients with BMI >30 kg/m² – 12–20 kcal/kg but not less than 1800 kcal/day to prevent ketosis. It was recommended to distribute the content of carbohydrates within a day as follows: breakfast 15–30 g, second breakfast 15–30 g, lunch 30–60 g, dinner 15–45 g, supper 30–60 g, second supper 10–15 g (on average, 150–175 g of carbohydrates per day). The time between food intakes should be not more than 2.5–3 hours, and the time between the last meal and the first meal the next day should be not more than 10 days. The consumption of fast carbohydrates and carbohydrates with a high glycemic index was excluded completely.

The starting daily dose of insulin in patients with normal BMI was 0.4 U/kg. In patients with excessive body weight, it was 0.5 U/kg. The distribution of basal and bolus types of insulin was 50/50%. In patients with basal-bolus insulin therapy, the starting dose of basal insulin was not less than 0.1 U/kg. Titration of insulin doses was performed every 1–2 days until the achievement of target indicators of glycemia under glycemia control not less than 4–6 times per day and at 3 am (at the stage of titration of long-acting insulin). The treatment included analogs of human insulin of ultra-short action (insulin aspart, insulin lispro) and long-acting insulin (insulin detemir, insulin glargine 100 U per 1 ml) [15].

The evaluation of preeclampsia in pregnant women was performed based on clinical recommendations [16]. Moderate preeclampsia was diagnosed in women with BP 140/90–159/109 mmHg and daily proteinuria > 0.3 g/day. Severe preeclampsia was diagnosed in women with BP ≥ 160/110 mmHg, daily proteinuria ≥ 5.0 g/L, and symptoms of multiple organ failure. The neonate’s weight was evaluated using percentile scales [17].

Statistical analysis was performed using an integral system for statistical analysis and data processing Statistica 10.0. The study results are presented as the mean for continuous values and percent for discreet values.

The characteristics of the group of pregnant women with MDM are presented in Table 2.

It should be mentioned that the genetic background in women with MDM had relatives with DM2 and DM1. Every fourth woman had acknowledged risk factors for carbohydrate metabolism disorder development during pregnancy.

The mean age of gestation at MDM onset was 16.8±7.9 weeks, and at GDM onset – 27.8±11.9 weeks. In 13 women, MDM was detected in the first half of pregnancy based on the results of stage I screening (fasting glucose tolerance test). The glucose level was 9.3±3.0 mmol/L. In six women, MDM diagnosis was verified based on the results of the oral glucose tolerance test two hours after glucose loading. The glucose level was 13.3±1.5 mmol/L. To evaluate the duration of metabolic disorders in women with MDM, the HbA1c test was performed, which showed 7.2±1.1% (a significantly long period of carbohydrate metabolism decompensation).

The analysis of weight-height indicators in women with MDM was performed. In 12 women, BMI was 32.6±7.0 kg/m²; in five patients, it was within physiological values (22.0±1.5 kg/m²), and two patients had body mass deficit (16.2±1.2 kg/m²).All patients with MDM and GDM were offered rational diet therapy. Patients with MDM were indicated insulin therapy at the gestation stage of 19.8±7.9 weeks. Thirteen women received insulin therapy in basal-bolus mode; five patients – only in bolus mode, and one patient received only long-acting insulin at 10 pm.

In patients with GDM, insulin therapy was indicated in 27.8% of cases and started at the age of gestation of 27.6±9.5 weeks [ 14.9;32.0]. Bolus insulin therapy was prescribed to 64.9% of women; basal-bolus – to 31.5% of women, and long-acting insulin was prescribed to 3.6% of women at evening hours. Insulin dose titration was performed according to the clinical recommendations protocol (fasting glucose level >5.1 mmol/L and postprandial blood glucose level > 6.7 mmol/L) [9]. In the group of women with excessive bodyweight, starting insulin dose was 44.0 [ 27.5;61.0] U, in women with obesity, it was 40.0 [ 25.5; 89.0] U, in women with normal BMI, it was 20.0 [ 14.5;21.5] U. The dynamics of daily insulin doses are presented in Table 3.

One of the most frequent complications during pregnancy, referred to as great obstetrical syndromes, is preeclampsia. Its incidence in the group of women with MDM was 36.8%, while in the group of women with GDM, it was observed in 15%.

Twelve patients with MDM had preterm delivery at 39.0±1.2 weeks. It could be associated with the fact that women with this pathology were followed in a specialized center. The rate of abdominal delivery in the group of women with MDM was 47.4% of cases. In 55.5% of patients, indications for cesarean section (CS) included such obstetrical and perinatal complications as preeclampsia and diabetic fetopathy associated with a mother’s hyperglycemia. In two cases, emergency CS was performed because of fetus vital activities impairments. Among patients with GDM, the incidence rate of CS was 52%. However, only 28.4% of surgeries were performed for indications that developed because of obstetrical and perinatal complications. The incidence rate of obstetrical and perinatal complications is presented in Table 4.

The structure of perinatal complications in newborns from mothers with MDM is presented in Table 5.

In 50% of patients with MDM in the postnatal period, carbohydrate metabolism disorders of various degrees were revealed. In three women, diabetes mellitus type 1 was diagnosed, in three women, diabetes mellitus type 2, and two women developed impaired glucose tolerance 6–12 months after delivery.

There are insufficient published data on the peculiarities of the course and outcomes of pregnancy and delivery in women with MDM. It is known that MDM onset is characterized by high hyperglycemia, requires emergency medical help, and can lead not only to perinatal but also to maternal death. This category of patients requires special medical attention because of the epidemiologic situation associated with the pandemic of the novel coronavirus infection. This provided a rationale for this study.

The major part of studies confirms the early onset of MDM in comparison with GDM. In this study, the mean age of gestation at MDM onset was 16.8±7.9 weeks, which was earlier in comparison with the data published by Mañé (2019), wherein the age of gestation at MDM onset was 21.4±8.9 weeks [18]. The obtained results agreed with other authors on the levels of HbA1c in women with MDM (> 6.5%). The study by Park (2015) showed that the HbA1c level in women with MDM was 6.8±0.9 vs 5.4±0.4% in women with GDM [19]. These results confirm the possibility of the application of this parameter as one criterion of MDM diagnostics and evaluation of the duration and severity of carbohydrate metabolism disorders. In most pregnant women in this study, MDM was verified by the results of the fasting glucose test or in the daytime in the first part of pregnancy. In seven pregnant women, MDM was detected during the oral glucose tolerance test. Wong (2013) in their study showed that fasting/stimulated glycemia levels during the oral glucose tolerance test were 6.4±1.8/11.4±2.4 mmol/L in women with MDM and 5.2±0.7/8.5±1.2 mmol/L in women with GDM [20].

The level of glycemia 9.3±3.0 mmol/L and HbA1c 7.2±1.1% in the group of women with MDM provided grounds for the prescription of intensive insulin therapy in 100% of cases. In some works [18][19][21], there were grounds for the indication of insulin therapy for women with MDM in 80–90% of cases. The level of glycemia >11 mmol/L in pregnant women requires additional examination to exclude DKA. If clinical and laboratory indicators of DKA are revealed, insulin therapy should be performed by the method of microfluidic injection following the instructions for the correction of water-electrolyte disorders, prevention of infectious complications, and control of the condition of the fetoplacental complex [15].

The study by Mañé (2019) showed that women with MDM had a high incidence rate of preterm deliveries (23.1% vs 6.7%), emergency abdominal deliveries (41.0% vs 19.5%), preeclampsia (22.0% vs 3.7%, p<0.01), and birth of large children to the age of gestation (40.0% vs 14.8%, p=0.08) in comparison with a group of women with GDM [18]. Wong (2013) confirmed an increased rate of perinatal complications in children whose mothers had MDM in comparison with mothers who had GDM: fetal macrosomia (25.9% vs 15.0%), neonatal hypoglycemia (11.7% vs 7.3%), shoulder dystocia (6.9% vs 0.7%). The general rate of unfavorable perinatal and antenatal outcomes was higher in the group of women with MDM (42.8% vs 30.7%) compared to the group of women with GDM [20].

In the present study, the rate of preeclampsia in the group of women with MDM was 36.8%, while in the group of women with GDM, it was 15%. Fetal macrosomia was observed more often in women with MDM (36.8%) than in women with GDM (17%). According to the studies included in the review, most authors highlight the increased rate of preterm deliveries in women with MDM compared to women with GDM. In the present study, the pregnancy term to delivery in women with MDM was 39.0±1.2 weeks. The pregnancy term to delivery close to physiological could be explained by the fact that women were followed in a specialized institution according to the protocol of examination and treatment.

According to clinical recommendations, all women who had MDM and GDM had to be examined 6–12 weeks after the delivery to specify the status of carbohydrate metabolism [9]. This examination is especially important in women with MDM with more manifested metabolic disorders. In this study, 50% of patients with MDM had carbohydrate metabolism disorders in the postpartum period, which agreed with the data published by Park et al., wherein in 73% of women with MDM, diabetes was verified after 6–8 weeks after the delivery, which exceeded the rate of carbohydrate metabolism disorders in women with GDM (4.3%) [19]. The obtained data demonstrate the necessity to follow strictly the recommendations on the reclassification of carbohydrate metabolism in women who had MDM during pregnancy.

To decrease the rate of obstetrical and perinatal complications in women with MDM, it is necessary to follow the recommendations: