Gestastional Diabetes

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Maternal and neonatal outcomes following a diabetic pregnancy within the context of HIV.

Int J Gynaecol Obstet. 2019 Dec;147(3):404-412

Authors: Soepnel LM, Nicolaou V, Huddle KRL, Klipstein-Grobusch K, Levitt NS, Norris SA

OBJECTIVE: To characterize the demographics, comorbidities, management, and outcomes of pregnant women with pre-gestational and gestational diabetes (GDM), including overt and true GDM, taking into account HIV infection and the influence of exposure to oral hypoglycemic agents (OHAs).
METHODS: A review of medical records of 1071 diabetic pregnancies (between 2012 and 2018) at a tertiary hospital in South Africa.
RESULTS: Of the women, 43% had GDM, 19% had type 1 diabetes (T1DM), and 38% had type 2 diabetes (T2DM). Each group had a mean initial body mass index (BMI) >25 kg/m2 . Despite poor initial HbA1c for pre-gestational groups, over 90% of the cohort achieved glycemic control by the time of delivery. The rate of prematurity was 30.9%. Perinatal mortality (PNM) was 5.1% for the pre-gestational group and 1.8% for GDM. Of the cohort, 23.9% was HIV infected. PNM was higher in the HIV-infected pregnancies (9.4%) than non-HIV exposed pregnancies (1.8%, P<0.001). The macrosomia rate was higher in the glibenclamide-exposed group than the insulin-alone group (12.2% vs 0%, P=0.025).
CONCLUSION: Obesity is a significant predictor for macrosomia and was high in all groups. In a low-/middle-income country setting with a high prevalence of HIV and high usage of OHAs as an alternative to insulin therapy, HIV might be associated with higher PNM and glibenclamide with increased rates of macrosomia, which warrants further exploration.

PMID: 31479156 [PubMed - indexed for MEDLINE]

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Methylation profile of genes involved in inflammation, in the blood from pregnancies with maternal preeclampsia due to untreated gestational diabetes mellitus.

Hormones (Athens). 2019 Jun;18(2):173-178

Authors: Halvatsiotis P, Tsokaki T, Chrelias C, Kassanos D, Domali E, Gazouli M, Dimitriadis G, Kalantaridou S

PURPOSE: To investigate DNA methylation changes in peripheral blood from patients with gestational diabetes mellitus (GDM) and preeclampsia (PE) due to poorly treated GDM.
METHODS: Eighteen pregnant women participated in the study: 6 with GDM, 6 with PE, and 6 healthy controls. The promoter methylation status of genes was profiled using the Human Inflammatory Response and Autoimmunity EpiTect Methyl II Signature PCR Array profiles. The results were validated with quantitative real-time polymerase chain reaction (qRT-PCR).
RESULTS: Fewer inflammation-related genes were significantly hypomethylated in PE cases compared to healthy subjects than in GDM cases. Some of the examined genes show different methylation patterns between GDM and PE.
CONCLUSIONS: The epigenetic changes observed in this study indicate that GDM and PE exhibit specific DNA methylation profiles, with possible clinical applications.

PMID: 31154656 [PubMed - indexed for MEDLINE]

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Metabolic Culprits in Obese Pregnancies and Gestational Diabetes Mellitus: Big Babies, Big Twists, Big Picture : The 2018 Norbert Freinkel Award Lecture.

Diabetes Care. 2019 05;42(5):718-726

Authors: Barbour LA

Pregnancy has been equated to a "stress test" in which placental hormones and growth factors expose a mother's predisposition toward metabolic disease, unleashing her previously occult insulin resistance (IR), mild β-cell dysfunction, and glucose and lipid surplus due to the formidable forces of pregnancy-induced IR. Although pregnancy-induced IR is intended to assure adequate nutrition to the fetus and placenta, in mothers with obesity, metabolic syndrome, or those who develop gestational diabetes mellitus, this overnutrition to the fetus carries a lifetime risk for increased metabolic disease. Norbert Freinkel, nearly 40 years ago, coined this excess intrauterine nutrient exposure and subsequent offspring developmental risk "fuel-mediated teratogenesis," not limited to only excess maternal glucose. Our attempts to better elucidate the causes and mechanisms behind this double-edged IR of pregnancy, to metabolically characterize the intrauterine environment that results in changes in newborn body composition and later childhood obesity risk, and to examine potential therapeutic approaches that might target maternal metabolism are the focus of this article. Rapidly advancing technologies in genomics, proteomics, and metabolomics offer us innovative approaches to interrogate these metabolic processes in the mother, her microbiome, the placenta, and her offspring that contribute to a phenotype at risk for future metabolic disease. If we are successful in our efforts, the researcher, endocrinologist, obstetrician, and health care provider fortunate enough to care for pregnant women have the unique opportunity to positively impact health outcomes not only in the short term but in the long run, not just in one life but in two-and possibly, for the next generation.

PMID: 31010942 [PubMed - indexed for MEDLINE]

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The role of adipokines in the pathogenesis of gestational diabetes mellitus.

Gynecol Endocrinol. 2019 Sep;35(9):737-751

Authors: de Gennaro G, Palla G, Battini L, Simoncini T, Del Prato S, Bertolotto A, Bianchi C

Gestational diabetes mellitus (GDM) is a complex condition whose physiopathology to date has not been completely clarified. Two major metabolic disorders, insulin resistance and β-cells dysfunction, play currently major role in pathogenesis of GDM. These elements are influenced by the amount of adipose tissue present before and/or during the pregnancy. Consequently, adipokines (adiponectin (APN), leptin (LPT), adipocyte fatty acid-binding protein, resistin, visfatin, omentin, vaspin, apelin, chemerin) secreted by adipose tissue, may contribute directly and/or indirectly, through the enhancement of chronic inflammation, aggravating insulin resistance and promoting GDM onset. This review aims to outline the potential physiopathological and prognostic role in GDM of adipokines, mainly APN and LPT.

PMID: 30990092 [PubMed - indexed for MEDLINE]

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Role of VEGF165b/VEGFTOTAL ratio in gestational diabetes mellitus.

Gynecol Endocrinol. 2019 Sep;35(9):811-814

Authors: Krishnasamy S, Ravi V, Rajaraman B, Kumar Thulasingam S, Dhevasena CS, Pathak A, Swaminathan K, Sundaresan M, Ayyappa KA, Arunkumar G, Kuppan G, Ramadas N, Vedantham S

Proper vascular function is important for well-being of mother and growing fetus. VEGFTOTAL, and VEGF165b levels and its vascular endothelial complications in gestational diabetes mellitus (GDM) together with the association of inflammation and advanced glycation end products (AGEs) are less studied. VEGF165b/VEGFTOTAL (VEGF RATIO) in GDM pregnant women was investigated in this study. Plasma VEGFTOTAL was lower in GDM (17.68 ± 1.30 pg/mL) compared to non-GDM (25.69 ± 1.40 pg/mL). VEGF165b, ICAM-1, and AGEs were higher in GDM (9.9 ± 1.4 pg/mL, 201.04 ± 7.85 µg/mL, and 10.40 ± 0.98 µg/mL, respectively) and lower in non-GDM (6.47 ± 0.70 pg/mL, 174.1 ± 7.11 µg/mL, and 4.71 ± 0.39 µg/mL, respectively). Compared to non GDM (0.25 ± 0.02), VEGF RATIO was higher in GDM (0.45 ± 0.04) and correlated with -ICAM-1 (r = 0.375, p < .001) and AGEs (r = 0.199, p < .05). Tertile stratification of VEGF RATIO implied that frequency of GDM increases with increasing tertiles of VEGF RATIO (p for trend <.001). Association of VEGF RATIO with GDM was significant even after adjusting for AGEs (OR = 1.279, CI = 1.118-1.462, p < .0010) but it lost its significance when adjusted for ICAM-1 (OR = 1.006, CI = 0.995-1.017, p = .308). VEGF RATIO plays an important role in GDM in association with vascular inflammation.

PMID: 30964350 [PubMed - indexed for MEDLINE]

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Neonatal and maternal outcome after frozen embryo transfer: Increased risks in programmed cycles.

Am J Obstet Gynecol. 2019 08;221(2):126.e1-126.e18

Authors: Ginström Ernstad E, Wennerholm UB, Khatibi A, Petzold M, Bergh C

BACKGROUND: Frozen embryo transfer is associated with better perinatal outcome regarding preterm birth and low birthweight, yet higher risk of large for gestational age and macrosomia compared to fresh transfer. Further, higher rates of hypertensive disorders in pregnancy are noted after frozen embryo transfer. Whether these differences are due to the protocol used in frozen cycles remains unknown.
OBJECTIVE: To analyze the obstetric outcome after frozen embryo transfer depending on protocol used. Comparison was also made for frozen vs fresh transfer and for frozen transfer vs spontaneous conception.
STUDY DESIGN: A population-based retrospective registry study including all singletons born after frozen embryo transfer in Sweden from 2005 to 2015. The in vitro fertilization register was cross-linked with the Medical Birth Register, the Register of Birth Defects, the National Patient Register, the Swedish Neonatal Quality Register, and the Prescribed Drug Register. Singletons after frozen embryo transfer were compared depending on the presence of a corpus luteum in the actual cycle. All frozen transfer singletons were also compared with fresh transfer and spontaneous conception singletons. Primary outcomes were preterm birth (<37 w), low birthweight (<2500 g), hypertensive disorders in pregnancy, and postpartum hemorrhage (>1000 mL). Crude and adjusted odds ratio with 95% confidence interval were calculated and adjustment made for relevant confounders.
RESULTS: A total of 9726 singletons were born after frozen embryo transfer (natural cycles, n = 6297; stimulated cycles, n = 1983; programmed cycles, n = 1446), 24,365 after fresh transfer, and 1,127,566 after spontaneous conception. No significant differences were noticed for preterm birth and low birthweight between the different protocols used in frozen embryo transfer. Compared to natural and stimulated frozen cycles, programmed frozen cycles were associated with a higher risk of hypertensive disorders in pregnancy (adjusted odds ratio, 1.78; 95% confidence interval, 1.43-2.21 and adjusted odds ratio, 1.61; 95% confidence interval, 1.22-2,10, respectively) and postpartum hemorrhage (adjusted odds ratio, 2.63; 95% confidence interval, 2.20-3.13 and adjusted odds ratio, 2.87; 95% confidence interval, 2.29-2.60, respectively). Moreover, higher risks for postterm birth (adjusted odds ratio, 1.59; 95% confidence interval, 1.27-2.01 and adjusted odds ratio, 1.98; 95% confidence interval, 1.47-2.68) and macrosomia (adjusted odds ratio, 1.62; 95% confidence interval, 1.26-2.09 and adjusted odds ratio, 1.40; 95% confidence interval, 1.03-1.90) were detected. There were no significant differences in any outcomes between stimulated and natural cycles. Frozen cycles in general compared to fresh cycles and compared to spontaneous conceptions showed neonatal and maternal outcomes in agreement with earlier studies.
CONCLUSION: No significant difference could be seen regarding preterm birth and low birthweight between the different protocols. However, higher rates of hypertensive disorders in pregnancy, postpartum hemorrhage, postterm birth, and macrosomia were detected in programmed cycles. Stimulated cycles had outcomes similar to natural cycles. These findings are important in view of the increasing use of frozen cycles and the new policy of freeze-all cycles in in vitro fertilization. The results suggest a link between the absence of corpus luteum and adverse obstetric outcomes.

PMID: 30910545 [PubMed - indexed for MEDLINE]

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A spontaneous pregnancy and successful delivery in a Chinese female with Silver-Russell syndrome accompanied by gestational diabetes mellitus.

Gynecol Endocrinol. 2019 Sep;35(9):752-755

Authors: Shi M, Ruan L, Shi X, Zhu Y, Qian Y, Dai Z, Wu C

Silver-Russell syndrome (SRS) is a heterogeneous disorder characterized by severe intrauterine and postnatal growth retardation and typical dysmorphic features including body asymmetry, relative macrocephaly, protruding forehead, and feeding difficulties. Previous descriptions of SRS focus on the management of specific issues in children. Herein, we present clinical and metabolic characteristics of an adult woman with SRS accompanied by gestational diabetes mellitus (GDM). Given the rare circumstances presented in our case, the emerging questions concerning the management of metabolic issues and fertility potential in adult SRS patient deserve more attention. Further, long-term follow up is essential to gain future insights into the natural history and optimal management in adulthood.

PMID: 30905204 [PubMed - indexed for MEDLINE]

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Suboptimal Nocturnal Glucose Control Is Associated With Large for Gestational Age in Treated Gestational Diabetes Mellitus.

Diabetes Care. 2019 05;42(5):810-815

Authors: Law GR, Alnaji A, Alrefaii L, Endersby D, Cartland SJ, Gilbey SG, Jennings PE, Murphy HR, Scott EM

OBJECTIVE: Continuous glucose monitoring (CGM) provides far greater detail about fetal exposure to maternal glucose across the 24-h day. Our aim was to examine the role of temporal glucose variation on the development of large for gestational age (LGA) infants in women with treated gestational diabetes mellitus (GDM).
RESEARCH DESIGN AND METHODS: We performed a prospective observational study of 162 pregnant women with GDM in specialist multidisciplinary antenatal diabetes clinics. Participants undertook 7-day masked CGM at 30-32 weeks' gestation. Standard summary indices and glycemic variability measures of CGM were calculated. Functional data analysis was applied to determine differences in temporal glucose profiles. LGA was defined as birth weight ≥90th percentile adjusted for infant sex, gestational age, maternal BMI, ethnicity, and parity.
RESULTS: Mean glucose was significantly higher in women who delivered an LGA infant (6.2 vs. 5.8 mmol/L, P = 0.025, or 111.6 mg/dL vs. 104.4 mg/dL). There were no significant differences in percentage time in, above, or below the target glucose range or in glucose variability measures (all P > 0.05). Functional data analysis revealed that the higher mean glucose was driven by a significantly higher glucose for 6 h overnight (0030-0630 h) in mothers of LGA infants (6.0 ± 1.0 mmol/L vs. 5.5 ± 0.8 mmol/L, P = 0.005, and 108.0 ± 18.0 mg/dL vs. 99.0 ± 14.4 mg/dL).
CONCLUSIONS: Mothers of LGA infants run significantly higher glucose overnight compared with mothers without LGA infants. Detecting and addressing nocturnal glucose control may help to further reduce rates of LGA in women with GDM.

PMID: 30765428 [PubMed - indexed for MEDLINE]

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Evidence in support of the International Association of Diabetes in Pregnancy study groups' criteria for diagnosing gestational diabetes mellitus worldwide in 2019.

Am J Obstet Gynecol. 2019 08;221(2):109-116

Authors: Hod M, Kapur A, McIntyre HD, FIGO Working Group on Hyperglycemia in Pregnancy, FIGO Pregnancy and Prevention of early NCD Committee

Gestational diabetes mellitus, the most frequent medical complication of pregnancy, affects 5-6% of women in the United States with the use of the currently predominant Carpenter-Coustan criteria, which still represent the preferred approach of the American College of Obstetricians and Gynecologists. Alternative criteria proposed by the International Association of Diabetes in Pregnancy Study Groups would likely increase gestational diabetes mellitus prevalence to 15-20%, because of both a 1-step testing policy and the requirement for only 1 elevated glucose value for diagnosis. Increasing gestational diabetes mellitus prevalence relates to older maternal age and the increasing prevalence of overweight and obesity. This increased gestational diabetes mellitus prevalence is consistent with 29.3% prevalence of prediabetes and 4.5% prevalence of known diabetes outside pregnancy in US adults from 20-44 years of age. Gestational diabetes mellitus according to the International Association of Diabetes in Pregnancy Study Groups criteria is associated with almost twice the risk of large-for-gestational-age babies, increased fetal adiposity, neonatal hyperinsulinemia and preeclampsia, and a 50% higher risk of preterm delivery and shoulder dystocia. The recent publication of the Hyperglycemia and Adverse Pregnancy Outcome Follow Up Study provides further evidence regarding the influence of gestational diabetes mellitus on long-term maternal and infant health. This study clearly demonstrates that hyperglycemia in pregnancy, untreated and identified post hoc by the International Association of Diabetes in Pregnancy Study Groups criteria, carries a 41.5% risk of maternal prediabetes (odds ratio, 3.72; 95% confidence interval, 3.09-4.47) and 10.7% risk of type 2 diabetes (odds ratio, 7.63; 95% confidence interval, 5.33-10.95) after 11.4 years of follow up. Gestational diabetes mellitus was also associated with higher rates of childhood overweight and obesity (prevalence 39.3% with maternal gestational diabetes mellitus; odds ratio, 1.5; 95% confidence interval, 1.56-2.44). This article places these findings in the context of other recent studies that have demonstrated that interventions that include lifestyle measures and/or metformin offer a >50% reduction in the risk of women with gestational diabetes mellitus experiencing the development of overt diabetes mellitus after their index gestational diabetes mellitus pregnancy. Although prevention of obesity and prediabetes in offspring by pregnancy treatment of gestational diabetes mellitus has not been demonstrated to date, we argue that the immediate pregnancy benefits and opportunities for long-term improvements in maternal health justify a reevaluation of the current ambivalent approach taken by the American College of Obstetricians and Gynecologists to gestational diabetes mellitus diagnosis, which currently allow for a choice of alternative criteria. The Carpenter-Coustan or National Diabetes Data Group criteria, listed as preferred criteria by American College of Obstetricians and Gynecologists, markedly limit the frequency of gestational diabetes mellitus in comparison with the International Association of Diabetes in Pregnancy Study Groups criteria and limit the opportunity for immediate and long-term follow up and treatment. We consider that new information from the Hyperglycemia and Pregnancy Outcome Follow Up Study and other recent publications on long-term maternal and offspring risk provides compelling arguments for a more comprehensive approach to the promotion of maternal and infant health through all the life cycle.

PMID: 30682358 [PubMed - indexed for MEDLINE]

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Predictive model for macrosomia using maternal parameters without sonography information.

J Matern Fetal Neonatal Med. 2019 Nov;32(22):3859-3863

Authors: Shigemi D, Yamaguchi S, Aso S, Yasunaga H

Objective: We aimed to develop new predictive models for excluding macrosomia using only maternal physical parameters, without sonographic examination. Methods: The present study retrospectively analyzed the medical records of pregnant women who delivered singleton infants at term at one obstetric hospital in an urban area in Japan from May 2005 to April 2017. We performed logistic regression analysis to predict macrosomia and created an integer risk scoring system based on the significant predictors. We also developed an alternative predictive regression model using machine learning with the random forest algorithm. Results: There were 203 cases of macrosomia among 15,263 eligible women. Although our scoring system had low specificity and positive predictive value, the negative predictive value for screening macrosomia was very high (0.996-1.000). The other model, using machine learning with the random forest algorithm to predict macrosomia, showed a negative predictive value of 0.99, which was similar to the results of our scoring system. Conclusions: Our integer scoring system is an easy and useful method for excluding macrosomia among pregnant women without sonographic examination.

PMID: 29852791 [PubMed - indexed for MEDLINE]

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Comparison of placental three-dimensional power Doppler indices and volume in the first and the second trimesters of pregnancy complicated by gestational diabetes mellitus.

J Matern Fetal Neonatal Med. 2019 Nov;32(22):3784-3791

Authors: Wong CH, Chen CP, Sun FJ, Chen CY

Objective: To compare the changes of placental three-dimensional power Doppler indices and volume in the first and the second trimesters of pregnancy with gestational diabetes mellitus (GDM). Methods: This was a prospective case-control study of singleton pregnancies with risk factors for GDM. Data on placental vascular indices including vascularization index (VI), flow index (FI), and vascularization flow index (VFI), as well as placental volume were obtained and analyzed during the first and the second trimesters between pregnant women with and without GDM. Results: Of the 155 pregnant women enrolled, 31 developed GDM and 124 did not. VI and VFI were significantly lower in the GDM group during the first and second trimesters (VI: p = .023, and VFI: p = .014 in the first trimester; VI: p = .049, and VFI: p = .031 in the second trimester). However, the placental volume was similar in both the groups during the first trimester, while it was significantly increased in the GDM group during the second trimester (p = .022). There were no significant differences in FI and uterine artery pulsatility index between the two groups. After adjustments in multivariate logistic regression analysis, significant differences were observed in the first trimester VFI (adjusted odds ratio (OR) 0.76, 95% confidence interval (CI) 0.61-0.93), second trimester VFI (adjusted or 0.83, 95%CI 0.71-0.96), and second trimester placental volume (adjusted or 1.03, 95%CI 1.01-1.05). Conclusions: Placental vascular indices can provide an insight into placental vascularization in GDM during early pregnancy. VFI rather than placental volume may be a sensitive sonographic marker in the first trimester of GDM placentas.

PMID: 29716432 [PubMed - indexed for MEDLINE]

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Noninvasive, continuous, real-time glucose measurements compared to reference laboratory venous plasma glucose values.

J Matern Fetal Neonatal Med. 2019 Oct;32(20):3393-3400

Authors: Hadar E, Chen R, Toledano Y, Tenenbaum-Gavish K, Atzmon Y, Hod M

Purpose: Current modalities for glucose monitoring are invasive and inconvenient. The search for a noninvasive technique is still ongoing, without a clinically viable product. The aim of our study was to evaluate the safety and accuracy of a novel non-invasive continuous glucometer - the Wizmi™ device. Methods: Prospective, observational, controlled clinical trial. We included healthy pregnant women designated to undergo a 3-hour oral glucose tolerance test. Each participant underwent synchronous and simultaneous glucose measurement by venous sampling of plasma glucose and non-invasive glucose by Wizmi device. Primary outcome was the accuracy of the Wizmi device as assessed by comparing between paired measurements, i.e. non-invasive glucose measurements by Wizmi versus standard plasma glucose levels, which were taken at the exact same time. Results: Thirty-two women underwent oral glucose tolerance test (OGTT), contributing 224 paired glucose measurements. Of the 224 paired measurements, all were within the clinically appropriate zones of the Clarke error grid analysis zones -208 (93%) in Zone A and 16 (7%) in zone B. Mean absolute relative difference of the Wizmi non-invasive glucose versus plasma glucose laboratory reference was 7.23% or 9.66 mg/dl. Overall, for all 224 paired measurements, across all Wizmi glucose ranges, the agreement was 86.6, 92.0, 97.8 and 99.5% for deviations within ±15, 20, 30, 40% (if glucose >80 mg/dl) or mg/dl (if glucose ≤80 mg/dl). Conclusions: Wizmi device is novel non-invasive continuous glucose monitor, safe to use, with overall high accuracy compared to a gold standard reference of plasma glucose.

PMID: 29635953 [PubMed - indexed for MEDLINE]

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Maternal Dyslipidaemia in Pregnancy with Gestational Diabetes Mellitus: Possible Impact on Foetoplacental Vascular Function and Lipoproteins in the Neonatal Circulation.

Curr Vasc Pharmacol. 2019;17(1):52-71

Authors: Contreras-Duarte S, Carvajal L, Fuenzalida B, Cantin C, Sobrevia L, Leiva A

Dyslipidaemia occurs in pregnancy to secure foetal development. The mother shows a physiological increase in plasma total cholesterol and Triglycerides (TG) as pregnancy progresses (i.e. maternal physiological dyslipidaemia in pregnancy). However, in some women pregnancy-associated dyslipidaemia exceeds this physiological adaptation. The consequences of this condition on the developing fetus include endothelial dysfunction of the foetoplacental vasculature and development of foetal aortic atherosclerosis. Gestational Diabetes Mellitus (GDM) associates with abnormal function of the foetoplacental vasculature due to foetal hyperglycaemia and hyperinsulinaemia, and associates with development of cardiovascular disease in adulthood. Supraphysiological dyslipidaemia is also detected in GDM pregnancies. Although there are several studies showing the alteration in the maternal and neonatal lipid profile in GDM pregnancies, there are no studies addressing the effect of dyslipidaemia in the maternal and foetal vasculature. The literature reviewed suggests that dyslipidaemia in GDM pregnancy should be an additional factor contributing to worsen GDM-associated endothelial dysfunction by altering signalling pathways involving nitric oxide bioavailability and neonatal lipoproteins.

PMID: 29149816 [PubMed - indexed for MEDLINE]

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