The Impact of Hypoglycemia and EPA and DHA Supplementation on Brain-Derived Neurotrophic Factor Level in Pregnant Women with Type 1 Diabetes: A Prospective Cohort Study.

BACKGROUND: In addition to its neuroprotective effect, Brain-derived neurotrophic factor (BDNF) also plays a role in glucose and lipid metabolism. This study aims: a) to find changes in the BDNF concentration during pregnancy in type 1 diabetes. b) to prove the effect of DHA and EPA supplementation on changes in BDNF concentrations c) to investigate the impact of hypoglycemia on BDNF concentration. SUBJECTS AND METHODS: The data from this study were from the PRE-HYPO cohort study. Twenty-one of them were on a standard diabetic diet enriched with EPA and DHA (EPA 120 mg/day and DHA 616 mg/day; Exposed group), and nineteen pregnant diabetic women were on the standard diabetic diet without EPA and DHA supplementation (Non-exposed group). In the first trimester of pregnancy, fifteen pregnant women developed hypoglycemia episodes (≤3.9 mmol/L; HYPO+ group), and twenty-five pregnant women did not have hypoglycemia episodes (HYPO- group). RESULTS: BDNF concentration significantly decreased during pregnancy from the first to the third trimester, in Non-exposed from 25.1 (22.0-30.2) to 22.1 (16.3-28.2), P<0.05, in the Exposed group from 22.1 (19.8-25.9) to 18.1 (14.8-18.9), P<0.01. Pregnant patients with hypoglycemia episodes (HYPO+ subgroup) had significantly higher BDNF in the third trimester of pregnancy [22.5 (20.6-28.4)] when compared with patients who did not develop hypoglycemia [16.3 (14.3-18.8), P<0.001]. In the third trimester of pregnancy, BDNF and n-6 PUFAs were associated with hypoglycemia (OR 1.818 95 % CI 1.079-3.003, P=0.025; OR 1.103 95 % CI 1.001-1.217, P=0.048). Total F.A.s were inversely associated with hypoglycemia (OR 0.969 95% CI 0.939-0.998, P=0.048). CONCLUSION: Pregnant women with hypoglycemia (HYPO+ group) had higher concentrations of BDNF in the first and third trimesters of pregnancy compared to those without hypoglycemia. An increase in body weight during pregnancy leads to a decrease in BDNF concentration.

THE ROLE OF LOW MOLECULAR WEIGHT HEPARIN IN WOMEN WITH HEREDITARY THROMBOPHILIA FOR GOOD PERINATAL OUTCOME.

The aim of the study was to establish the importance of low molecular weight heparin (LMWH) treatment for good pregnancy outcome in patients with hereditary thrombophilia. This retrospective study included 70 patients with inherited thrombophilia who gave birth at Zagreb University Hospital Center in the period from January 2014 to January 2015. Fifty-seven women were treated and 13 women were not treated with LMWH. Perinatal outcome was significantly better in women with hereditary thrombophilia who were treated with heparin during pregnancy as compared with women without LMWH (p=0.006). Regardless of heparin therapy, patients with hereditary thrombophilia alone had a significantly better perinatal outcome as compared with women who, along with hereditary thrombophilia, had a history of habitual abortions (p=0.035) or intrauterine fetal death (p=0.033). Women treated with heparin had better perinatal outcome if they were without a history of recurrent or non-recurrent fetal loss (p=0.088). In the group without LMWH, perinatal outcome was significantly better in women with no history of habitual abortions as compared with women with recurrent miscarriages (p=0.047). Administration of LMWH is justified in women with hereditary thrombophilia and a history of adverse perinatal outcome.

Cognitive Function during and after Pregnancy and One-Year Postpartum in Type 1 Diabetes: A Longitudinal Study.

BACKGROUND: This study aims to compare the cognitive function of women with T1DM during and after pregnancy, as well as one year post-delivery. Additionally, it aims to investigate the impacts of leptin and body mass index on cognitive function. METHODS: A prospective longitudinal cohort study was conducted involving 64 pregnant women with T1DM. Cognitive function was assessed using a cognitive assessment battery during the first trimester, immediately after delivery, and one year postpartum for the final assessment. This program evaluates a wide range of cognitive abilities and provides a comprehensive cognitive well-being score (high-moderate-low), identifying strengths and weaknesses in reasoning, memory, attention, coordination, and perception. RESULTS: The average age of the participants was 30.9 years, with a mean diabetes duration of 14.9 years. Pregnant women with a BMI of 30 kg/m2 or higher faced an increased risk of reduced cognitive function, memory, and reasoning. Additionally, mothers with lower overall cognitive function and memory levels had significantly higher concentrations of leptin in their blood. CONCLUSIONS: Cognitive functions-particularly reasoning and attention-are adversely affected in women with T1DM during pregnancy and shortly after delivery. Elevated BMI and leptin levels can be linked to worse cognitive outcomes in this population.

Successful delivery of fetus with fetal inherited thrombophilia after two fetal deaths.

A pregnant woman with inherited thrombophilia (factor II mutation--20210A) had two late pregnancy losses. The first pregnancy was not well documented, but the second pregnancy was complicated by fetal thrombophilia and umbilical artery thrombosis, proven after fetal death. During the third pregnancy enoxaparine was introduced in the therapy and early amniocentesis was performed. Fetal thrombophilia was proven again. Early delivery was induced and performed with no complications, resulting in a live healthy infant. A history of miscarriages or recurrent fetal loss should raise suspicion of thrombophilia as a potential cause. It is debatable whether amniocentesis in pursuit of fetal thrombophilia should be performed and whether this will lead to a better perinatal outcome. When fetal thrombophilia is diagnosed, an earlier induction of delivery should be considered, taking into account the fetal extrauterine viability. The aforementioned approach of early delivery in cases of inherited fetal thrombophilia could be a possible solution for better perinatal outcomes.

Relationship of Glucose, C-peptide, Leptin, and BDNF in Maternal and Umbilical Vein Blood in Type-1 Diabetes.

The study aimed to determine the relationship between glucose, C-peptide, brain-derived neurotrophic factor (BDNF), and leptin between mother and fetus and neonatal weight. METHODS: In the prospective observational cohort study, we included 66 women with type-1 diabetes mellitus (T1DM). According to the z-score for neonatal weight, patients were divided into healthy-weight neonates (n = 42) and overweight neonates (n = 24). The maternal blood samples were taken during pregnancy and cesarean section when the umbilical vein blood sample was also withdrawn. The maternal vein sera were analyzed for fasting glucose, C-reactive protein (CRP), leptin, BDNF, TSH, FT3, and FT4. The umbilical vein sera were analyzed for glucose, C-peptide, leptin, TSH, thyroid-stimulating protein (FT3), free thyroxine (FT4), and BDNF concentration. The neonatologist measured the skinfold thickness on the third day of neonatal life. RESULTS: A strong correlation was confirmed between maternal and umbilical vein glucose concentration and maternal glucose and C-peptide in umbilical vein blood. A negative correlation was found between the concentration of BDNF in the umbilical vein and glucose in maternal blood. A strong correlation was seen between BMI and maternal blood leptin concentration, neonatal fat body mass, and umbilical vein blood leptin concentration. Higher BMI elevated BDNF, and TSH increase the odds for overweight neonates in the first trimester of pregnancy. Maternal higher leptin concentration in the first trimester decrease the odds of overweight neonates. CONCLUSIONS: Maternal glucose concentrations affect the fetus's glucose, C-peptide, and BDNF concentrations. Leptin levels increase in maternal blood due to increased body mass index, and in the neonate, fat body mass is responsible for increased leptin concentrations.

Awakened Beta-Cell Function Decreases the Risk of Hypoglycemia in Pregnant Women with Type 1 Diabetes Mellitus.

Diabetes in pregnancy creates many problems for both the mother and child. Pregnant women with type 1 diabetes experience more frequent hypoglycemic and hyperglycemic episodes. This study aimed to determine the risk of clinically significant biochemical hypoglycemia (CSBH) by HbA1c, fasting C-peptide, mean plasma glucose (PG), and insulin dose in pregnant women type 1 diabetes mellitus according to each trimester of the pregnancy. METHODS: We conducted a prospective observational study of 84 pregnant women with type 1 diabetes in an academic hospital. To present the hypoglycemia, we divided the participants into two groups: those who did not have clinically significant biochemical hypoglycemia (CSBH-; n = 30) and those who had clinically significant biochemical hypoglycemia (CSBH+; n = 54). RESULTS: In the first, second, and third trimesters, the duration of T1DM, fasting C-peptide, and mean glucose concentration was inversely associated with CSBH. CONCLUSIONS: Insulin overdose is the most common risk factor for hypoglycemia. In pregnant women with type 1 diabetes with elevated fasting C-peptide levels, the insulin dose should be diminished to reduce the risk of hypoglycemia.

Positive Association between Preserved C-Peptide and Cognitive Function in Pregnant Women with Type-1 Diabetes.

This study focused on the cognitive function of women with type 1 diabetes in pregnancy. We investigated risk factors for a low cognitive score such as age, duration of Diabetes, BMI, subclinical hypothyroidism, cardiovascular autonomic neuropathy, the impact of hypo-/hyperglycemia, and C-peptide preservation. Material and methods. Seventy-eight pregnant women with type 1 diabetes (age 31.1 ± 5.4 years, diabetes duration 14.3 ± 8.9 years) were included in the study. Cognitive function was assessed in different domains, such as reasoning, memory, attention, coordination, and perception. Results. The cognitive test values ≥400 were considered high scores, and values <400 were considered low. Relative risks for low scores for general cognitive function were associated with increased BMI > 25 kg/m2 2.208 (95% CI 1.116−4.370), HbA1c > 6.5% RR 0.774 (95% CI 0.366−1.638), subclinical hypothyroidism RR 3.111 (95% CI 1.140−8.491), and impaired cardiovascular autonomic neuropathy RR 2.250 (95% CI 1.000−5.062). Pregnant women with a lower score for general cognitive function had higher BMI and higher leptin levels. Preserved C-peptide reduces the risk for cognitive impairment (RR 0.297 (95% CI 0.097−0.912)) in pregnant women with type 1 diabetes Conclusion. BMI > 25 kg/m2, subclinical hypothyroidism, and cardiovascular autonomic neuropathy are associated with increased risk, and postprandial C-peptide preservation with reduced risk for cognitive impairment in pregnant women with type 1 diabetes.

N-3 PUFA and Pregnancy Preserve C-Peptide in Women with Type 1 Diabetes Mellitus.

Type 1 diabetes (T1DM) is an autoimmune disease characterized by the gradual loss of ß-cell function and insulin secretion. In pregnant women with T1DM, endogenous insulin production is absent or minimal, and exogenous insulin is required to control glycemia and prevent ketoacidosis. During pregnancy, there is a partial decrease in the activity of the immune system, and there is a suppression of autoimmune diseases. These changes in pregnant women with T1DM are reflected by Langerhans islet enlargement and improved function compared to pre-pregnancy conditions. N-3 polyunsaturated fatty acids (n-3 PUFA) have a protective effect, affect ß-cell preservation, and increase endogenous insulin production. Increased endogenous insulin production results in reduced daily insulin doses, better metabolic control, and adverse effects of insulin therapy, primarily hypoglycemia. Hypoglycemia affects most pregnant women with T1DM and is several times more common than that outside of pregnancy. Strict glycemic control improves the outcome of pregnancy but increases the risk of hypoglycemia and causes maternal complications, including coma and convulsions. The suppression of the immune system during pregnancy increases the concentration of C-peptide in women with T1DM, and n-3 PUFA supplements serve as the additional support for a rise in C-peptide levels through its anti-inflammatory action.

Supplementation of EPA and DHA in pregnant women with type 1 diabetes mellitus.

BACKGROUND/OBJECTIVE: Lower proportions of n-3 PUFAs have been observed in neonates born to diabetic mothers. We aimed to investigate the association between DHA and EPA supplementation during pregnancy complicated with type 1 diabetes on concentration and proportion of fatty acids in maternal and foetal blood. SUBJECTS AND METHODS: We conducted a prospective randomized, single-blinded, placebo-controlled trial of 111 eligible pregnant women with type 1 diabetes and presented the results of 84 (intervention arm and control arm comprised 42 participants each) of them who successfully finished the trial in an academic hospital. The initiation of EPA and DHA supplementation or placebo started at randomization visit on gestational week 11-12. Blood samples were taken on the first (screening) visit to the clinic (1st trimester, between 8th and 10th gestational week, GW), then in the second trimester (19-24th GW) and third trimester (30th-33rd GW). On the delivery day, a blood sample was taken on fasting just before birth. The umbilical vein blood sample was taken shortly after the delivery. RESULTS: We found a significant increase in the intervention group when compared the first and the third trimester for n-3 PUFAs concentration, 4.3 mg/L (3.3-7.6): 10.0 mg/L (7.1-13.7), p < .001. In the intervention group, the concentration of DHA in maternal vein serum was 11.4 mg/L (7.7-17.5), and in umbilical vein serum, it was 5.1 mg/L (3.0-7.7), which was significantly higher than that in the control group, maternal vein serum: median 9.2 mg/L(6.0-12.3), p = .03 and umbilical vein serum: median 3.4 mg/L (2.1-5.6), p = .009. CONCLUSION: The increased weight gain in pregnancy and concentration and proportions of DHA, n-3 PUFAs with a decreased proportion of AA, n-6 PUFAs, and AA/DHA ratio in maternal and umbilical vein serum summarize the effect of supplementation with EPA and DHA.

[Pregnancies and deliveries in patients with Charcot-Marie-Tooth disease]. / Trudnoca i porodaj u bolesnica s hereditarnom senzomotornom polineuropatijom (Charcot-Marie-Tooth).

Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth (CMT) disease, is a spectrum of disorders caused by a specific mutation in one of several myelin genes, which results in defects in myelin structure, maintenance and formation. Affected individuals show progressive distal limb atrophy and weakness, often with gait disturbance and deformity of feet and hands. There have been few studies on how CMT disease can affect pregnancy, birth and the newborn. CMT is an independent risk factor for complications during pregnancy and delivery. Patients with CMT have more operative deliveries, malpresentations and postpartum bleeding than the general obstetric population. It is not clear whether the increased prevalence of malpresentation is related to fetal disease, although the disorder typically does not present until later in childhood. Postpartum bleeding from atony may be related to the disease effect on uterine adrenergic nerves. Exacerbation of CMT disease can occur in pregnancy, an effect that may be mediated by increased plasma progesterone level. Observations in an animal model were consistent with these findings as the administration of progesterone resulted in a more progressive neuropathy, while a progesterone antagonist slowed the disease progression. We treated two patients with CMT (type 5 and type X1) at our Department. Both of them had normal course of pregnancy until delivery. Emergency cesarean section was performed in both cases; in one because of malpresentation, contracted pelvis and signs of impending fetal asphyxiation during the second stage of delivery, and in the other one based on neurologist indication. In the latter, uterine atony with profuse postpartum bleeding occurred immediately after cesarean section and emergency hysterectomy was performed according to clinical status.

[Guidelines for diagnostics and treatment of arterial hypertension. Practical recommendations of the Croatian Working Group for Hypertension. Consideration on the ESH-ESC 2007 guidelines]. / Smjernice za dijagnosticiranje i lijecenje arterijske hipertenzije. Prakticne preporuke hrvatske radne skupine i osvrt na smjernice ESH/ESC 2007.

ESH/ECS guidelines for diagnostics and treatment of arterial hypertension 2007 is a basic paper for all physicians who treat hypertensive patients. Since publishing, this article has been the most cited medical paper. According to ESH/ECS guidelines some local peculiarities in each country should be considered when diagnosing and treating hypertensive patients. Practical recommendations of the Croatian working group for the diagnostics and treatment of hypertension are in agreement with ESH/ECS guidelines. However, few additional issues are added and further discussed in this paper (hypertensive crisis, treatment of hypertension in patients undergoing dialysis and in renal transplanted patients, role of family physicians, role of nurse). We believe that this paper will contribute better control of hypertension in Croatia. All medical societies and institutions that took part in writing this document, have to consider this paper as an official statement.

[Hypertension in pregnancy]. / Hipertenzija i trudnoca.

Pregnancy in hypertension is not a single entity, and currently several classifications exist. Most often used is the updated classification of the American College of Obstetricians and Gynecologists, which classifies hypertension into chronic hypertension, preeclampsia-eclampsia, preeclampsia superposed on chronic hypertension, and gestational hypertension. Preeclampsia occurs in about 7% of pregnant women. Primigravida have increased risk for preeclampsia. Preeclampsia frequency in sisters was 37%, in daughters 26%, in granddaughters 16%, an in daughters in law only 6%, which points to the strong hereditary association. Although basic clinical changes in preeclampsia appear in the second part of pregnancy, some haemodynamic and biochemical abnormalities may be observed earlier. Besides haemodynamic abnormalities in the mother, one of the main characteristics of preeclampsia is uteroplacental circulation insufficiency, and consequent intrauterine growth restriction. Basic alterations in preeclampsia occur due to inadequate trophoblast migration and lack of spiral artery physiologic transformation. In preeclampsia, musculoelastic layer of spiral arterioles is preserved, therefore their lumen stays narrow during the entire pregnancy, ad their wall sensitive to vasoconstrictive factors. Currently, the most convincing and most comprehensive is the hypothesis on generalized endothelial dysfunction as the underlying pathophysiological mechanisms. Preeclampsia is an illness that develops due to vasoconstriction and reduced perfusion, particularly in essential organs. HELLP syndrome is a multiple system disease whose pathogenesis has not yet been completely explained. In HELLP syndrome endothelial vascular cells are damaged, resulting in intravascular platelet activation. Frequency of HELLP syndrome is about 0.2-0.6% of all pregnancies, and 4-12% of those with preeclampsia. HELLP syndrome is an acronym for H = haemolysis, EL = elevated liver enzymes and LP = low platelet count. Risk factors are multiple pregnancy, mother' age over 25 years, white race, and poor perinatal outcome in previous pregnancies. Preeclampsia treatment is a great challenge for every physician, but also the subject of numerous discussion because there is no consensus on which drug would be the best for the treatment and prevention of preeclampsia. Generally accepted opinion is that the cut-off blood pressure level, when antihypertensive therapy should be initiated, is diastolic blood pressure over 110 mmHg. However, it should not be decreased below 90-100 mmHg in order not to jeopardize uteroplacental circulation, which is in preeclampsia and eclampsia already significantly reduced. Termination of pregnancy is the definitive treatment for preeclampsia and eclampsia.

Birth weight of healthy newborns in Zagreb area, Croatia.

The aim of this study was to assess birth weight of healthy newborns from the City of Zagreb and Zagreb County, Croatia. Birth weights of healthy newborns, born at the Department of Obstetrics and Gynecology, University Hospital Center "Zagreb" in the year 2001, were included into analysis. Since there were only few newborns in the 22nd-27th week of gestation, they were excluded from the study. Small number of data points was also noticed in 28th-36th week of gestation, and was supplemented with the data from the years 2000, 2002 and 2003. The method of analysis used in this study was described by Altman and Chitty (Br. J. Obstet. Gynaecol., 101 (1994) 29). After the application of well defined exclusion criteria, the final sample consisted of 4252 newborns. Percentile values for the four groups of newborns (male gender-primipara, male gender-multipara, female gender-primipara, female gender-multipara) were defined, yielding highest birth weight values in the male gender-multipara group (50th percentile of 40th gestational week was 3551.3 g), while female gender-primipara newborns were the lightest among the four sub-samples studied (50th percentile of 40th gestational week was 3399.9 g). New percentile values for percentile curves plotting are presented here and recommended for use in the clinical practice.

Perinatal Health Statistics as the Basis for Perinatal Quality Assessment in Croatia.

CONTEXT: Perinatal mortality indicators are considered the most important measures of perinatal outcome. The indicators reliability depends on births and deaths reporting and recording. Many publications focus on perinatal deaths underreporting and misclassification, disabling proper international comparisons. OBJECTIVE: Description of perinatal health care quality assessment key indicators in Croatia. METHODS: Retrospective review of reports from all maternities from 2001 to 2014. RESULTS: According to reporting criteria for birth weight ≥500 g, perinatal mortality (PNM) was reduced by 31%, fetal mortality (FM) by 32%, and early neonatal mortality (ENM) by 29%. According to reporting criteria for ≥1000 g, PNM was reduced by 43%, FM by 36%, and ENM by 54%. PNM in ≥22 weeks' (wks) gestational age (GA) was reduced by 28%, FM by 30%, and ENM by 26%. The proportion of FM at 32-36 wks GA and at term was the highest between all GA subgroups, as opposed to ENM with the highest proportion in 22-27 wks GA. Through the period, the maternal mortality ratio varied from 2.4 to 14.3/100,000 live births. The process indicators have been increased in number by more than half since 2001, the caesarean deliveries from 11.9% in 2001 to 19.6% in 2014. CONCLUSIONS: The comprehensive perinatal health monitoring represents the basis for the perinatal quality assessment.

Redefinition of gestational diabetes mellitus: implications for laboratory practice in Croatia.

An increasing prevalence of gestational diabetes has become a very challenging task in prenatal care worldwide. International Association of Diabetes and Pregnancy Study Groups (IADPSG) has recently issued recommendations on the diagnosis and classification of hyperglycaemia in pregnancy. These recommendations, the first to provide harmonised, evidence-based criteria for the diagnosis and classification of diabetes in pregnancy, are currently being discussed and accepted worldwide by the relevant authorities. As the acceptance of the proposed criteria has major implications for both clinical and laboratory settings, a concerted action towards necessary changes in practice has to be carefully planned and adjusted to national health-care specificities. IADPSG criteria have been strongly advocated by the Croatian Perinatology Society, resulting in a new strategy for the detection and diagnosis of hyperglycaemic disorders in pregnancy. To address the respective laboratory requirements, in April 2012, the Croatian Chamber of Medical Biochemists appointed a Working Group to provide a standardised procedure for the diagnosis of gestational diabetes, applicable to all laboratories involved in prenatal care, in both primary and specialised health-care facilities. In this paper we discuss key laboratory-related issues regarding succesful implementation of the IADPSG criteria in Croatia.

Abdominal hernias in pregnancy.

A hernia is an area of weakness or complete disruption of the fibromuscular tissues of the body wall. In addition to the body wall, hernias can occur in the diaphragm, pelvic wall, perineum, pelvic floor, and internal abdominal viscera (hernias through omental or mesenteric defects, ligaments and folds). Surgical repair of different types of hernia is the most common general surgical procedure with more than 20 million hernioplasties performed each year. Abdominal wall hernias are not common during pregnancy. Hernias can be symptomless or have minimal symptoms, including slight discomfort or pain. Such hernias are not life-threatening and should be controlled on regular basis. After spontaneous delivery and uterine involution, they should be repaired on an elective basis. It is of utmost importance for a clinician to diagnose emergent situations, which include incarceration, strangulation and perforation caused by hernia because consultation with a surgeon and emergency operation are mandatory. There is still no consensus for irreducible hernia during pregnancy, but complications during pregnancy outweigh elective operation. Therefore, hernioplasty is recommended during pregnancy, especially in early gestation.