Gestational diabetes is driven by microbiota-induced inflammation months before diagnosis.

OBJECTIVE: Gestational diabetes mellitus (GDM) is a condition in which women without diabetes are diagnosed with glucose intolerance during pregnancy, typically in the second or third trimester. Early diagnosis, along with a better understanding of its pathophysiology during the first trimester of pregnancy, may be effective in reducing incidence and associated short-term and long-term morbidities. DESIGN: We comprehensively profiled the gut microbiome, metabolome, inflammatory cytokines, nutrition and clinical records of 394 women during the first trimester of pregnancy, before GDM diagnosis. We then built a model that can predict GDM onset weeks before it is typically diagnosed. Further, we demonstrated the role of the microbiome in disease using faecal microbiota transplant (FMT) of first trimester samples from pregnant women across three unique cohorts. RESULTS: We found elevated levels of proinflammatory cytokines in women who later developed GDM, decreased faecal short-chain fatty acids and altered microbiome. We next confirmed that differences in GDM-associated microbial composition during the first trimester drove inflammation and insulin resistance more than 10 weeks prior to GDM diagnosis using FMT experiments. Following these observations, we used a machine learning approach to predict GDM based on first trimester clinical, microbial and inflammatory markers with high accuracy. CONCLUSION: GDM onset can be identified in the first trimester of pregnancy, earlier than currently accepted. Furthermore, the gut microbiome appears to play a role in inflammation-induced GDM pathogenesis, with interleukin-6 as a potential contributor to pathogenesis. Potential GDM markers, including microbiota, can serve as targets for early diagnostics and therapeutic intervention leading to prevention.

Equity in coronavirus disease 2019 vaccine development and deployment.

The coronavirus disease 2019 pandemic exposed weaknesses in multiple domains and widened gender-based inequalities across the world. It also stimulated extraordinary scientific achievement by bringing vaccines to the public in less than a year. In this article, we discuss the implications of current vaccination guidance for pregnant and lactating women, if their exclusion from the first wave of vaccine trials was justified, and if a change in the current vaccine development pathway is necessary. Pregnant and lactating women were not included in the initial severe acute respiratory syndrome coronavirus 2 vaccine trials. Therefore, perhaps unsurprisingly, the first vaccine regulatory approvals have been accompanied by inconsistent advice from public health, governmental, and professional authorities around the world. Denying vaccination to women who, although pregnant or breastfeeding, are fully capable of autonomous decision making is a throwback to a paternalistic era. Conversely, lack of evidence generated in a timely manner, upon which to make an informed decision, shifts responsibility from research sponsors and regulators and places the burden of decision making upon the woman and her healthcare advisor. The World Health Organization, the Task Force on Research Specific to Pregnant Women and Lactating Women, and others have highlighted the long-standing disadvantage experienced by women in relation to the development of vaccines and medicines. It is uncertain whether there was sufficient justification for excluding pregnant and lactating women from the initial severe acute respiratory syndrome coronavirus 2 vaccine trials. In future, we recommend that regulators mandate plans that describe the development pathway for new vaccines and medicines that address the needs of women who are pregnant or lactating. These should incorporate, at the outset, a careful consideration of the balance of the risks of exclusion from or inclusion in initial studies, patient and public perspectives, details of "developmental and reproductive toxicity" studies, and approaches to collect data systematically from participants who are unknowingly pregnant at the time of exposure. This requires careful consideration of any previous knowledge about the mode of action of the vaccine and the likelihood of toxicity or teratogenicity. We also support the view that the default position should be a "presumption of inclusion," with exclusion of women who are pregnant or lactating only if justified on specific, not generic, grounds. Finally, we recommend closer coordination across countries with the aim of issuing consistent public health advice.

Nutrition Management of Gestational Diabetes Mellitus.

Medical nutrition therapy (MNT) is the bedrock for the management of gestational diabetes mellitus (GDM). Several different types of dietary approaches are used globally, and there is no consensus among the various professional groups as to what constitutes an ideal approach. The conventional approach of limiting carbohydrates at the cost of increasing energy from the fat source may not be most optimal. Instead, allowing higher levels of complex, low-to-medium glycaemic index carbohydrates and adequate fibre through higher consumption of vegetables and fruits seems more beneficial. No particular diet or dietary protocol is superior to another as shown in several comparative studies. However, in each of these studies, one thing was common - the intervention arm included more intensive diet counselling and more frequent visits to the dieticians. For MNT to work, it is imperative that diet advice and nutrition counselling is provided by a dietician, which is easy to understand and use and includes healthy food options, cooking methods, and practical guidance that empower and motivate to make changes towards a healthy eating pattern. Various simple tools to achieve these objectives are available, and in the absence of qualified dieticians, they can be used to train other health care professionals to provide nutrition counselling to women with GDM. Given the impact of GDM on the future health of the mother and offspring, dietary and lifestyle behaviour changes during pregnancy in women with GDM are not only relevant for immediate pregnancy outcomes, but continued adherence is also important for future health.

Inositols: From Established Knowledge to Novel Approaches.

Myo-inositol (myo-Ins) and D-chiro-inositol (D-chiro-Ins) are natural compounds involved in many biological pathways. Since the discovery of their involvement in endocrine signal transduction, myo-Ins and D-chiro-Ins supplementation has contributed to clinical approaches in ameliorating many gynecological and endocrinological diseases. Currently both myo-Ins and D-chiro-Ins are well-tolerated, effective alternative candidates to the classical insulin sensitizers, and are useful treatments in preventing and treating metabolic and reproductive disorders such as polycystic ovary syndrome (PCOS), gestational diabetes mellitus (GDM), and male fertility disturbances, like sperm abnormalities. Moreover, besides metabolic activity, myo-Ins and D-chiro-Ins deeply influence steroidogenesis, regulating the pools of androgens and estrogens, likely in opposite ways. Given the complexity of inositol-related mechanisms of action, many of their beneficial effects are still under scrutiny. Therefore, continuing research aims to discover new emerging roles and mechanisms that can allow clinicians to tailor inositol therapy and to use it in other medical areas, hitherto unexplored. The present paper outlines the established evidence on inositols and updates on recent research, namely concerning D-chiro-Ins involvement into steroidogenesis. In particular, D-chiro-Ins mediates insulin-induced testosterone biosynthesis from ovarian thecal cells and directly affects synthesis of estrogens by modulating the expression of the aromatase enzyme. Ovaries, as well as other organs and tissues, are characterized by a specific ratio of myo-Ins to D-chiro-Ins, which ensures their healthy state and proper functionality. Altered inositol ratios may account for pathological conditions, causing an imbalance in sex hormones. Such situations usually occur in association with medical conditions, such as PCOS, or as a consequence of some pharmacological treatments. Based on the physiological role of inositols and the pathological implications of altered myo-Ins to D-chiro-Ins ratios, inositol therapy may be designed with two different aims: (1) restoring the inositol physiological ratio; (2) altering the ratio in a controlled way to achieve specific effects.

Clinical update on COVID-19 in pregnancy: A review article.

The data pertaining to the COVID-19 pandemic has been rapidly evolving since the first confirmed case in December 2019. This review article presents a comprehensive analysis of the current data in relation to COVID-19 and its effect on pregnant women, including symptoms, disease severity and the risk of vertical transmission. We also review the recommended management of pregnant women with suspected or confirmed COVID-19 and the various pharmacological agents that are being investigated and may have a role in the treatment of this disease. At present, it does not appear that pregnant women are at increased risk of severe infection than the general population, although there are vulnerable groups within both the pregnant and nonpregnant populations, and clinicians should be cognizant of these high-risk groups and manage them accordingly. Approximately 85% of women will experience mild disease, 10% more severe disease and 5% critical disease. The most common reported symptoms are fever, cough, shortness of breath and diarrhea. Neither vaginal delivery nor cesarean section confers additional risks, and there is minimal risk of vertical transmission to the neonate from either mode of delivery. We acknowledge that the true effect of the virus on both maternal and fetal morbidity and mortality will only be evident over time. We also discuss the impact of social isolation can have on the mental health and well-being of both patients and colleagues, and as clinicians, we must be mindful of this and offer support as necessary.

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

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.

Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT): a multicentre international randomised controlled trial.

BACKGROUND: Pregnant women with type 1 diabetes are a high-risk population who are recommended to strive for optimal glucose control, but neonatal outcomes attributed to maternal hyperglycaemia remain suboptimal. Our aim was to examine the effectiveness of continuous glucose monitoring (CGM) on maternal glucose control and obstetric and neonatal health outcomes. METHODS: In this multicentre, open-label, randomised controlled trial, we recruited women aged 18-40 years with type 1 diabetes for a minimum of 12 months who were receiving intensive insulin therapy. Participants were pregnant (≤13 weeks and 6 days' gestation) or planning pregnancy from 31 hospitals in Canada, England, Scotland, Spain, Italy, Ireland, and the USA. We ran two trials in parallel for pregnant participants and for participants planning pregnancy. In both trials, participants were randomly assigned to either CGM in addition to capillary glucose monitoring or capillary glucose monitoring alone. Randomisation was stratified by insulin delivery (pump or injections) and baseline glycated haemoglobin (HbA1c). The primary outcome was change in HbA1c from randomisation to 34 weeks' gestation in pregnant women and to 24 weeks or conception in women planning pregnancy, and was assessed in all randomised participants with baseline assessments. Secondary outcomes included obstetric and neonatal health outcomes, assessed with all available data without imputation. This trial is registered with ClinicalTrials.gov, number NCT01788527. FINDINGS: Between March 25, 2013, and March 22, 2016, we randomly assigned 325 women (215 pregnant, 110 planning pregnancy) to capillary glucose monitoring with CGM (108 pregnant and 53 planning pregnancy) or without (107 pregnant and 57 planning pregnancy). We found a small difference in HbA1c in pregnant women using CGM (mean difference -0·19%; 95% CI -0·34 to -0·03; p=0·0207). Pregnant CGM users spent more time in target (68% vs 61%; p=0·0034) and less time hyperglycaemic (27% vs 32%; p=0·0279) than did pregnant control participants, with comparable severe hypoglycaemia episodes (18 CGM and 21 control) and time spent hypoglycaemic (3% vs 4%; p=0·10). Neonatal health outcomes were significantly improved, with lower incidence of large for gestational age (odds ratio 0·51, 95% CI 0·28 to 0·90; p=0·0210), fewer neonatal intensive care admissions lasting more than 24 h (0·48; 0·26 to 0·86; p=0·0157), fewer incidences of neonatal hypoglycaemia (0·45; 0·22 to 0·89; p=0·0250), and 1-day shorter length of hospital stay (p=0·0091). We found no apparent benefit of CGM in women planning pregnancy. Adverse events occurred in 51 (48%) of CGM participants and 43 (40%) of control participants in the pregnancy trial, and in 12 (27%) of CGM participants and 21 (37%) of control participants in the planning pregnancy trial. Serious adverse events occurred in 13 (6%) participants in the pregnancy trial (eight [7%] CGM, five [5%] control) and in three (3%) participants in the planning pregnancy trial (two [4%] CGM and one [2%] control). The most common adverse events were skin reactions occurring in 49 (48%) of 103 CGM participants and eight (8%) of 104 control participants during pregnancy and in 23 (44%) of 52 CGM participants and five (9%) of 57 control participants in the planning pregnancy trial. The most common serious adverse events were gastrointestinal (nausea and vomiting in four participants during pregnancy and three participants planning pregnancy). INTERPRETATION: Use of CGM during pregnancy in patients with type 1 diabetes is associated with improved neonatal outcomes, which are likely to be attributed to reduced exposure to maternal hyperglycaemia. CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy. This study is the first to indicate potential for improvements in non-glycaemic health outcomes from CGM use. FUNDING: Juvenile Diabetes Research Foundation, Canadian Clinical Trials Network, and National Institute for Health Research.

Have we neglected the role of fetal endothelium in transplacental transport?

Maternal-to-fetal transfer of nutrient and other substances occurs across the placental barrier (PB) which is made up of endothelial cells (EC) on the fetal side and the syncytiotrophoblast (STB) on the maternal side. Numerous studies were conducted to explore the transport characteristics across the STB layer, which is also considered as the major resistance for maternal-to-fetal exchange of materials. In contrast the layer of EC has received very little attention if at all. A recently developed viable co-culture model of the PB revealed significant resistance of the EC layer for maternal-to-fetal transfer of glucose. This argues for a major contribution of the EC to overall transplacental transfer of nutrients. Accordingly, it is recommended to fill the void of knowledge and expand our understanding on the role of the feto-placental endothelium for transplacental transport characteristics.

Pharmacological Management of Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is one of the most common morbidities complicating pregnancy, with short- and long-term consequences to the mothers, fetuses, and newborns. Management and treatment are aimed to achieve best possible glycemic control, while avoiding hypoglycemia and ensuring maternal and fetal safety. It involves behavioral modifications, nutrition and medications, if needed; concurrent with maternal and fetal surveillance for possible adverse outcomes. This review aims to elaborate on the pharmacological options for GDM therapy. We performed an extensive literature review of different available studies, published during the last 50 years, concerning pharmacological therapy for GDM, dealing with safety and efficacy, for both fetal and maternal morbidity consequences; as well as failure and success in establishing appropriate metabolic and glucose control. Oral medication therapy is a safe and effective treatment modality for GDM and in some circumstances may serve as first-line therapy when nutritional modifications fail. When oral agents fail to establish glucose control then insulin injections should be added. Determining the best oral therapy in inconclusive, although it seems that metformin is slightly superior to glyburide, in some aspects. As for parenteral therapy, all insulins listed in this article are considered both safe and effective for treatment of hyperglycemia during pregnancy. Importantly, a better safety profile, with similar efficacy is documented for most analogues. As GDM prevalence rises, there is a need for successful monitoring and treatment for patients. Caregivers should know the possible and available therapeutic options.

CONCEPTT: Continuous Glucose Monitoring in Women with Type 1 Diabetes in Pregnancy Trial: A multi-center, multi-national, randomized controlled trial - Study protocol.

BACKGROUND: Women with type 1 diabetes strive for optimal glycemic control before and during pregnancy to avoid adverse obstetric and perinatal outcomes. For most women, optimal glycemic control is challenging to achieve and maintain. The aim of this study is to determine whether the use of real-time continuous glucose monitoring (RT-CGM) will improve glycemic control in women with type 1 diabetes who are pregnant or planning pregnancy. METHODS/DESIGN: A multi-center, open label, randomized, controlled trial of women with type 1 diabetes who are either planning pregnancy with an HbA1c of 7.0 % to ≤10.0 % (53 to ≤ 86 mmol/mol) or are in early pregnancy (<13 weeks 6 days) with an HbA1c of 6.5 % to ≤10.0 % (48 to ≤ 86 mmol/mol). Participants will be randomized to either RT-CGM alongside conventional intermittent home glucose monitoring (HGM), or HGM alone. Eligible women will wear a CGM which does not display the glucose result for 6 days during the run-in phase. To be eligible for randomization, a minimum of 4 HGM measurements per day and a minimum of 96 hours total with 24 hours overnight (11 pm-7 am) of CGM glucose values are required. Those meeting these criteria are randomized to RT- CGM or HGM. A total of 324 women will be recruited (110 planning pregnancy, 214 pregnant). This takes into account 15 and 20 % attrition rates for the planning pregnancy and pregnant cohorts and will detect a clinically relevant 0.5 % difference between groups at 90 % power with 5 % significance. Randomization will stratify for type of insulin treatment (pump or multiple daily injections) and baseline HbA1c. Analyses will be performed according to intention to treat. The primary outcome is the change in glycemic control as measured by HbA1c from baseline to 24 weeks or conception in women planning pregnancy, and from baseline to 34 weeks gestation during pregnancy. Secondary outcomes include maternal hypoglycemia, CGM time in, above and below target (3.5-7.8 mmol/l), glucose variability measures, maternal and neonatal outcomes. DISCUSSION: This will be the first international multicenter randomized controlled trial to evaluate the impact of RT- CGM before and during pregnancy in women with type 1 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01788527 Registration Date: December 19, 2012.

Insulin detemir versus glyburide in women with gestational diabetes mellitus.

AIM: To evaluate the safety, efficacy and pregnancy outcomes of insulin detemir (IDet) versus glyburide treatment in women with gestational diabetes mellitus (GDM). METHODS: We conducted a retrospective cohort study of women with GDM who were treated with either glyburide or IDet for GDM in a university-affiliated tertiary hospital. RESULTS: Ninety-one patients with GDM were enrolled, 62 were administered glyburide and 29 IDet. Maternal age, pregestational body mass index (BMI) and rate of abnormal oral glucose tolerance test (OGTT) blood glucose values were not significantly different between groups. Good glycemic control rates were comparable. Hypoglycemic episodes were reported only in the glyburide group (19.4% versus 0%, p = 0.01). Maternal weight gain during pregnancy was significantly higher among women in the glyburide group (8.8 ± 5.1 kg, p < 0.001) compared to those in the IDet group (2.1 ± 19.9 kg, p = 0.71). CONCLUSIONS: To the best of our knowledge, this is the first study on IDet treatment in patients with GDM. By our preliminary results, IDet is a viable treatment option in women with GDM. Further large prospective studies are needed to determine the efficacy and safety of IDet in GDM patients.

Results from the International Consensus Conference on myo-inositol and D-chiro-inositol in Obstetrics and Gynecology--assisted reproduction technology.

A substantial body of research on mammalian gametogenesis and human reproduction has recently investigated the effect of myo-inositol (MyoIns) on oocyte and sperm cell quality, due to its possible application to medically assisted reproduction. With a growing number of both clinical and basic research papers, the meaning of several observations now needs to be interpreted under a solid and rigorous physiological framework. The 2013 Florence International Consensus Conference on Myo- and D-chiro-inositol in obstetrics and gynecology has answered a number of research questions concerning the use of the two stereoisomers in assisted reproductive technologies. Available clinical trials and studies on the physiological and pharmacological effects of these molecules have been surveyed. Specifically, the physiological involvement of MyoIns in oocyte maturation and sperm cell functions has been discussed, providing an answer to the following questions: (1) Are inositols physiologically involved in oocyte maturation? (2) Are inositols involved in the physiology of spermatozoa function? (3) Is treatment with inositols helpful within assisted reproduction technology cycles? (4) Are there any differences in clinical efficacy between MyoIns and D-chiro-inositol? The conclusions of this Conference, drawn depending on expert panel opinions and shared with all the participants, are summarized in this review paper.

In pain thou shalt bring forth children: the peak-and-end rule in recall of labor pain.

Childbirth is usually the most painful event of a mother's life, and resonates in individual and collective memory for years. The current study examined the relationship between the experience of labor pain and its recollection 2 days and 2 months after delivery. We found that despite the exceptional physical and emotional experiences of childbirth, the memory of the pain involved in labor was biased toward the average of the peak pain and the end pain, whereas the duration of the delivery had a relatively negligible effect on the recollected intensity of pain. A comparison of mothers whose labor ended with or without epidural analgesia corroborated previous findings that the level of pain toward the end of an experience greatly influences the way the overall experience is remembered. Although both short- and long-term retention of memories of labor exhibited the peak-and-end effect, having given birth before weakened the effect 2 months after delivery.

Counterpoint: Establishing consensus in the diagnosis of GDM following the HAPO study.

The International Association of Diabetes in Pregnancy Study Groups (IADPSG) recommended a new protocol of 1-step testing with a 75 g oral glucose tolerance test for gestational diabetes in 2010. Since that time, these recommendations have been carefully scrutinized and accepted by a variety of organizations, but challenged or rejected by others. In the current review, we present more details regarding the background to the development of the IADPSG recommendations and seek to place them in context with the available epidemiologic and randomized controlled trial data. In this "counterpoint," we also provide specific rebuttal for errors of fact and disputed contentions provided by Long and Cundy in their 2013 article in Current Diabetes Reports.

Managing couples with recurrent miscarriage: A narrative review and practice recommendations.

There is significant variation in practice when managing couples with recurrent miscarriage (RM), with guidelines differing on the definition of RM, recommended investigations, and treatment options. In the absence of evidence-based guidance, and following on from a paper by the authors-FIGO Good Practice Recommendations on the use of progesterone in the management of recurrent first-trimester miscarriage-this narrative review aims to propose a global holistic approach. We present graded recommendations based on best available evidence.