Pathophysiology from preconception, during pregnancy, and beyond.

Gestational diabetes is the most common medical complication in pregnancy. Historically, gestational diabetes was considered a pregnancy complication involving treatment of rising glycaemia late in the second trimester. However, recent evidence challenges this view. Pre-pregnancy and pregnancy-specific factors influence gestational glycaemia, with open questions regarding roles of non-glycaemic factors in the aetiology and consequences of gestational diabetes. Varying patterns of insulin secretion and resistance in early and late pregnancy underlie a heterogeneity of gestational diabetes in the timing and pathophysiological subtypes with clinical implications: early gestational diabetes and insulin resistant gestational diabetes subtypes are associated with a higher risk of pregnancy complications. Metabolic perturbations of early gestational diabetes can affect early placental development, affecting maternal metabolism and fetal development. Fetal hyperinsulinaemia can affect the development of multiple fetal tissues, with short-term and long-term consequences. Pregnancy complications are prevented by managing glycaemia in early and late pregnancy in some, but not all women with gestational diabetes. A better understanding of the pathophysiology and heterogeneity of gestational diabetes will help to develop novel management approaches with focus on improved prevention of maternal and offspring short-term and long-term complications, from pre-conception, throughout pregnancy, and beyond.

Epidemiology and management of gestational diabetes.

Gestational diabetes is defined as hyperglycaemia first detected during pregnancy at glucose concentrations that are less than those of overt diabetes. Around 14% of pregnancies globally are affected by gestational diabetes; its prevalence varies with differences in risk factors and approaches to screening and diagnosis; and it is increasing in parallel with obesity and type 2 diabetes. Gestational diabetes direct costs are US$1·6 billion in the USA alone, largely due to complications including hypertensive disorders, preterm delivery, and neonatal metabolic and respiratory consequences. Between 30% and 70% of gestational diabetes is diagnosed in early pregnancy (ie, early gestational diabetes defined by hyperglycaemia before 20 weeks of gestation). Early gestational diabetes is associated with worse pregnancy outcomes compared with women diagnosed with late gestational diabetes (hyperglycaemia from 24 weeks to 28 weeks of gestation). Randomised controlled trials show benefits of treating gestational diabetes from 24 weeks to 28 weeks of gestation. The WHO 2013 recommendations for diagnosing gestational diabetes (one-step 75 gm 2-h oral glucose tolerance test at 24-28 weeks of gestation) are largely based on the Hyperglycemia and Adverse Pregnancy Outcomes Study, which confirmed the linear association between pregnancy complications and late-pregnancy maternal glycaemia: a phenomenon that has now also been shown in early pregnancy. Recently, the Treatment of Booking Gestational Diabetes Mellitus (TOBOGM) trial showed benefit in diagnosis and treatment of early gestational diabetes for women with risk factors. Given the diabesity epidemic, evidence for gestational diabetes heterogeneity by timing and subtype, and advances in technology, a life course precision medicine approach is urgently needed, using evidence-based prevention, diagnostic, and treatment strategies.

Development of a semi-automated tool to measure fetal abdominal wall thickness during ultrasound at 20 weeks' gestation.

OBJECTIVES: To develop a semi-automated tool for measuring fetal abdominal wall thickness (AWT). To validate the software using images captured by other centers and create a nomogram for fetal AWT between 18 and 20 weeks. METHODS: A semiautomated tool that measured AWT was developed using images captured at the routine 20-week morphology scan. The software was developed using digital images captured routinely during scans of low-risk women. Inter- and intraobserver reliability was assessed between manual and semi-automated measures. The tool was validated using images acquired from other centers. Linear regression and quadratic polynomials were used to create a nomogram for AWT. RESULTS: The semi-automated tool was able to measure AWT in all images. Interoperator reliability was 0.90 and 0.97 (P < 0.05) for manual and semi-automated methods, respectively. Measurement agreement varied between three operators from moderate to excellent (0.77, 0.87, 0.92), with overall agreement being good (0.85). The tool could be successfully applied to 89% of images from other centers. A nomogram was generated for AWT measurements of fetuses at 18-20 weeks in normal, low risk mothers. CONCLUSION: Semi-automated measurement of AWT was feasible using images captured during the routine 20-week scan. This approach had lower inter- and intraobserver variability compared to manual measurement.

Vulnerabilities and reparative strategies during pregnancy, childbirth, and the postpartum period: moving from rhetoric to action.

Maternal outcomes throughout pregnancy, childbirth, and the postnatal period are influenced by interlinked and interdependent vulnerabilities. A comprehensive understanding of how various threats and barriers affect maternal and perinatal health is critical to plan, evaluate and improve maternal health programmes. This paper builds on the introductory paper of the Series on the determinants of maternal health by assessing vulnerabilities during pregnancy, childbirth, and the postnatal period. We synthesise and present the concept of vulnerability in pregnancy and childbirth, and map vulnerability attributes and their dynamic influence on maternal outcomes in early and late pregnancy and during childbirth and the postnatal period, with a particular focus on low-income and middle-income countries (LMICs). We summarise existing literature and present the evidence on the effects of various reparative strategies to improve pregnancy and childbirth outcomes. Lastly, we discuss the implications of the identified vulnerability attributes and reparative strategies for the efforts of policymakers, healthcare professionals, and researchers working towards improving outcomes for women and birthing people in LMICs.

Effects of treating subclinical hypothyroidism in pregnancy in India: Are we treating too many for little gain? A retrospective cohort study.

OBJECTIVE: To assess the impact of treatment of subclinical hypothyroidism (SCH) on short-term pregnancy outcomes. METHOD: Data from 4526 consecutive women with singleton pregnancies who delivered between January 2015 and December 2017 were analyzed. SCH was defined as a thyroid-stimulating hormone (TSH) level between 2.5 and 10 mU/mL with normal free thyroxine. Of those with SCH, some were treated but others were not. These two groups were compared using χ2 and Student t tests for categorical and continuous variables, respectively. Multiple logistic regression models, adjusted for maternal age, body mass index, parity, gestation at TSH measurement, and gestational diabetes mellitus status, were used to investigate the effect of treatment on pregnancy and neonatal outcomes. RESULTS: In all, 1227 (27.1%) of 4526 women had SCH, of whom 393 (32.0%) were treated. The mean age and body mass index were similar in both groups. The mean gestation at measuring of TSH was 11.7 ± 6.5 weeks. There was no significant difference in pregnancy or neonatal outcomes between the two groups. A sub-group analysis when SCH was defined as TSH 4.0 mU/mL or greater showed a higher rate of large for gestational age and lower rates of low birth weight and small for gestational age in the treated group. CONCLUSIONS: The prevalence of SCH based on the international guidelines threshold is high in India. Treatment of SCH did not show any difference in pregnancy and neonatal outcomes in this study.

Uptake, Engagement and Acceptance, Barriers and Facilitators of a Text Messaging Intervention for Postnatal Care of Mother and Child in India-A Mixed Methods Feasibility Study.

This study aimed to test the feasibility and to identify barriers and facilitators towards adherence of a text messaging intervention for postnatal care in India. Mixed methods research involving both quantitative and qualitative methods were used. A survey questionnaire for feasibility and focus group interviews to identify the barriers and facilitators to the intervention were conducted. The top three reasons for activation of service were: helped the new mother to understand the changes (95%); provided continuation of care (90%) and clarified conflicting information (89%). Over 90% read the messages daily. 80% were happy with the message frequency. About 75% shared the content with others. The main reasons for non-activation were: 30% had technical issues, 15% did not think it would be useful, 17% did not have time to activate and for 5%, husbands made the decision. These findings were triangulated through the qualitative focus groups. The main themes identified via the focus groups were: (1) reliable, current information; (2) issues and themes well aligned with new mothers' needs and priorities; (3) expanded the repertoire of information sources available; and (4) high-quality accessible information. The satisfaction and trust rates were high. This technology may be useful for health information intervention in specific postnatal areas.

Altered levels of neurobiological biomarkers at the interface of depression and gestational diabetes mellitus in Asian Indian women.

AIM: Gestational diabetes mellitus (GDM) might predispose the mothers to depression. Studies have reported the role of biomarkers either in GDM or depression, but very few have examined them in GDM with depression. The present study profiled the circulating levels of brain-derived neurotrophic factor (BDNF), Beta Endorphin (BE) and nesfatin-1 in women with GDM (with and without depression). METHODS: 160 pregnant women at 24-28 weeks of pregnancy (NGT/GDM with & without depression, n = 40 each) were randomly selected from the ongoing STRiDE (STratification of Risk of Diabetes in Early pregnancy) study. Depression score was derived using PHQ-9 questionnaire and ELISA was used to quantify the biomarkers. RESULTS: Circulatory levels of BDNF, BE and nesfatin-1 were lower in GDM women with or without depression compared to NGT without depression, however, nesfatin-1 levels were higher in NGT with depression. Notably, GDM with depression had the lowest levels of BDNF and BE. Both BDNF and BE levels were negatively correlated with depression, 1 h and 2 h plasma glucose. Regression analysis confirmed that each standard deviation decreases in BDNF and BE were independently associated with higher odds of GDM with or without depression even after adjusting for potential confounders. CONCLUSION: Our study has identified altered levels of a panel of neurobiological biomarkers (BDNF/BE/nesfatin-1) in those with combined GDM and depression. BDNF/BE could be potential biomarkers to assess the higher risk of coexisting depression and GDM.

COVID-19-related anxiety and concerns expressed by pregnant and postpartum women-a survey among obstetricians.

This paper from India describes anxieties that pregnant and postpartum women reported to obstetricians during the COVID-19 pandemic. Of the 118 obstetricians who responded to an online survey, most had been contacted for concerns about hospital visits (72.65%), methods of protection (60.17%), the safety of the infant (52.14%), anxieties related to social media messages (40.68%) and contracting the infection (39.83%). Obstetricians felt the need for resources such as videos, websites and counselling skills to handle COVID-related anxiety among perinatal women.

Intrafetal laser for midtrimester TRAP sequence-experience from a single center.

OBJECTIVE: To report our experience and evaluate outcomes in monochorionic pregnancies with Twin Reversed Arterial Perfusion sequence with intrafetal laser therapy. METHODS: Retrospective review of records of all pregnancies with TRAP sequence treated by intrafetal laser therapy between 2011 January and 2015 December that were retrieved and analysed. RESULTS: Electronic search of the scan database retrieved 57 cases of TRAP sequence during the study period, 7 triplets and 50 monochorionic twins. Intrafetal laser was done in 27 cases, 22 cases of twins and 5 cases of triplets. In the twins group, median gestational age at intervention was 22.5 weeks, the earliest done at 16.3 weeks. The median gestational age at delivery and birth weight was 37 weeks and 2.5 Kgs. The median procedure and delivery interval was 14 weeks. Live birth rate was 17/22 (77%) the pump survival rate was 16/22 (73%). Pregnancies with non-surviving pump were 5 in numbers (5/22). A repeat procedure was warranted in one case. In the triplet group, median gestational age at intervention, delivery and procedure delivery interval was 18, 35 and 17 weeks. CONCLUSION: Intrafetal laser is simple, effective and the treatment of choice to interrupt the vascular supply to acardiac twin.

Gestational Diabetes Mellitus Postpartum Follow-Up Testing: Challenges and Solutions.

One in every 4 pregnancies is affected by hyperglycemia, of which 90% is gestational diabetes mellitus (GDM). Women with GDM are at a high risk of developing both short- and long-term complications. Various studies have shown the heightened risk of type 2 diabetes among women with GDM. Despite clear evidence from published literature about the substantial risk that GDM imposes on women after delivery, rates of postpartum follow up have been low in most parts of the world. Several reasons, such as lack of awareness among health-care professionals and patient-related barriers, such as emotional stress and adjusting to motherhood, have been cited as reasons for poor follow-up rates. To address these issues and come up with solutions to improve postpartum follow-up rates, it is important to understand these barriers both from the patient and the health-care system points of view. In this review, we have summarized some of the key issues contributing to the low postpartum follow-up rates and have discussed possible strategies to tackle them. Use of proactive reminder systems, such as postal service, telephone call, short messaging service and e-mail, recall registries for GDM and utilization of mobile health technology are some of the key strategies that have been discussed in this review. A brief note on the Women in India with GDM Strategy project, which developed a model of care for GDM in resource-constrained settings and adopted several strategies that led to a 95.8% postpartum follow up, has also been presented.

Increased fetal adiposity prior to diagnosis of gestational diabetes in South Asians: more evidence for the 'thin-fat' baby.

AIMS/HYPOTHESIS: Gestational diabetes mellitus (GDM) is associated with an increased future risk of obesity in the offspring. Increased adiposity has been observed in the newborns of women with GDM. Our aim was to examine early fetal adiposity in women with GDM. METHODS: Obstetric and sonographic data was collated for 153 women with GDM and 178 controls from a single centre in Chennai, India. Fetal head circumference (HC), abdominal circumference (AC), femur length (FL) and biparietal diameter (BPD) were recorded at 11, 20 and 32 weeks. Anterior abdominal wall thickness (AAWT) as a marker of abdominal adiposity at 20 and 32 weeks was compared between groups. Adjustments were made for maternal age, BMI, parity, gestational weight gain, fetal sex and gestational age. RESULTS: Fetuses of women with GDM had significantly higher AAWT at 20 weeks (ß 0.26 [95% CI 0.15, 0.37] mm, p < 0.0001) despite lower measures of HC, FL, BPD and AC. AAWT remained higher in the fetuses of women with GDM at 32 weeks (ß 0.48 [0.30, 0.65] mm, p < 0.0001) despite similar measures for HC, FL, BPD and AC between groups. Both groups had similar birthweights at term. There was an independent relationship between fasting plasma glucose levels and AAWT after adjustment as described above. CONCLUSIONS/INTERPRETATION: A 'thin but fat' phenotype signifying a disproportionate increase in adiposity despite smaller or similar lean body mass was observed in the fetuses of mothers with GDM, even at 20 weeks, thus pre-dating the biochemical diagnosis of GDM. Increased AAWT may serve as an early marker of GDM.

Physical activity patterns and gestational diabetes outcomes - The wings project.

OBJECTIVE: To compare physical activity (PA) patterns in pregnant woman with and without gestational diabetes (GDM) and to assess the effects of an exercise intervention on change in PA patterns, blood glucose levels and pregnancy outcomes in GDM women. METHODS: For the first objective, PA patterns were studied in 795 pregnant women with and without GDM. For the second objective, the Women in India with Gestational Diabetes Strategy-Model of Care (WINGS-MOC) intervention were evaluated in 151 women out of 189 with GDM. PA was assessed using a validated questionnaire and a pedometer. Changes in PA patterns, glycemic parameters and neonatal outcomes were evaluated. RESULTS: Overall, only 10% of pregnant women performed recommended levels of PA. Women with GDM were significantly more sedentary compared to those without GDM (86.2 vs. 61.2%, p<0.001). After the MOC was implemented in women with GDM, there was a significant improvement in PA and a decrease in sedentary behaviour amongst women (before MOC, moderate activity: 15.2%, sedentary: 84.8% vs. after MOC-moderate: 26.5%, sedentary: 73.5%; p<0.001), and an increase in their daily step count from 2206/day to 2476/day (p<0.001). Fasting 1 and 2-h postprandial glucose values significantly decreased (p<0.001 for all). Sedentary behaviour was associated with a fourfold higher risk (p=0.02), and recreational walking with 70% decreased risk, of adverse neonatal outcomes (p=0.04) after adjusting for potential confounders. CONCLUSIONS: PA levels are inadequate amongst this group of pregnant women studied i.e. those with and without GDM. However, a low-cost, culturally appropriate MOC can bring about significant improvements in PA in women with GDM. These changes are associated with improved glycemic control and reduction in adverse neonatal outcomes.

Association of Soluble (Pro) Renin Receptor with Gestational Diabetes Mellitus.

OBJECTIVE: There is a need to identify biomarkers for gestational diabetes mellitus (GDM). Recently the soluble pro-renin receptor (s[Pro]RR) has been shown to be associated with GDM. We investigated the association of s(Pro) RR levels in Asian Indians with GDM. METHODS: We recruited 222 pregnant females, 147 without GDM (non-GDM) and 75 with GDM visiting antenatal clinics in Tamilnadu in South India. We included singleton pregnancy and excluded those with pre-existing diabetes mellitus or hypertension. Oral glucose tolerance tests (OGTTs) were performed, and GDM was diagnosed using the International Association of Diabetes and Pregnancy Study Group criteria. s(Pro)RR was measured by enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristic (ROC) curves were used to identify s(Pro) RR cut-off points to identify GDM. RESULTS: The mean levels of the s(Pro)RR were significantly higher in subjects with GDM (34.0 ± 12 ng/mL, P<.001) compared to non-GDM (21.4 ± 6.5 ng/mL). The proportions of subjects with GDM were 11 (15%) in the first tertile of s(Pro)RR (<19.61 ng/mL), 20 (27%) in the second (19.62-26.8 ng/mL), and 44 (59%) in the third tertile (>26.8 ng/mL). In multiple logistic regression analysis, s(Pro)RR showed a significant association with GDM (odds ratio [OR]: 1.201, 95% confidence interval [CI]: 1.065-1.355, P = .003) after adjusting for potential confounders. A s(Pro)RR cut-off of 23.3 ng/mL had a C statistic of 0.828 (95% CI: 0.738-0.918, P<.001), sensitivity of 68%, and specificity of 70% to identify GDM. CONCLUSIONS: s(Pro)RR levels are higher in females with GDM, and this could be used as a potential biomarker.

Protein tyrosine phosphatase SHP2 mediates chronic insulin-induced endothelial inflammation.

OBJECTIVE: Insulin promotes adhesion of leukocytes to the endothelium through increased expression of surface adhesion molecules. We determined whether src-homology domain-2-containing protein tyrosine phosphatase 2 (SHP2), a downstream effecter of insulin signaling, is involved in insulin-induced endothelial inflammation. METHODS AND RESULTS: In human umbilical vein-derived endothelial cells, treatment with insulin (100 nmol/L) increased Tyr(542) phosphorylation, activity, and subsequently expression of SHP2. Increase in SHP2 accompanied a parallel decrease in the availability of the anti-inflammatory molecule, NO. This consequently enhanced the expression of cell adhesion molecules. Decrease in NO index was caused by endothelial NO synthase (eNOS) uncoupling and increased arginase activity. Among the 2 isoforms, insulin treatment induced the expression of arginase II. Inactivation of endogenous SHP2 via NSC87877 [8-hydroxy-7-(6-sulfonapthalen-2-yl)-diazenyl-quinoline-5-sulfonic acid] and its knockdown by small interfering RNA decreased arginase activity by blocking arginase II expression; however, it failed to restore eNOS coupling. Inactivation of SHP2 also abrogated insulin-mediated leukocyte adhesion by blocking the expression of adhesion molecules. Finally, downregulation of endogenous arginase II blocked insulin-mediated endothelial inflammation. CONCLUSIONS: SHP2 mediates chronic insulin-induced endothelial inflammation by limiting the production of NO in an eNOS-independent and arginase-II-dependent manner.