Appendiceal Neuroendocrine Neoplasms: an Update for 2023.

PURPOSE OF REVIEW: To summarize the literature from the last 5 years on treatment of appendiceal neuroendocrine neoplasms (aNEN). Furthermore, to evaluate the prognostic significance of lymph node metastases, indications for adjuvant treatment, and challenges of the current follow-up regimen. RECENT FINDINGS: Simple appendectomy is sufficient in tumors < 1 cm while extended surgery is indicated in tumors > 2 cm. In a multicenter study of aNENs measuring 1-2 cm, extended surgery offered no significant prognostic advantage and is now limited to incomplete tumor resection or high-grade G2 or G3 aNEN. Follow-up remains debatable, as the use of imaging and biomarkers lacks validation. While surgical procedure is well established in aNEN tumors < 1 cm and > 2 cm, the need for extended surgery in aNEN tumors 1-2 cm is questionable. Future studies should address the prognostic impact of lymph node metastases and the optimal design and duration of follow-up.

Pre-analytical diagnostic differences despite high adherence to guidelines for gestational diabetes mellitus.

Regional variations in the prevalence of gestational diabetes mellitus (GDM) have been found across Denmark. The objectives of this exploratory survey were to evaluate adherence to the national guideline for screening and diagnosing GDM and to identify variations in pre-analytical or analytical factors, which could potentially contribute to variations in GDM prevalence across regions. In a national interview-based survey, obstetric departments and laboratories throughout Denmark handling GDM screening or diagnostic testing were invited to participate. Survey questionnaires were completed through personal interviews. In total, 21 of 22 identified obstetric departments and 44 of 45 identified laboratories participated. Adherence to guideline among obstetric departments ranged 67-100% and uniformity in laboratory procedures was high. However, the gestational age at the time of late diagnostic testing with oral glucose tolerance test (OGTT) varied considerably, with 48% (10/21) of departments testing outside the recommended 24-28 weeks' gestation. Procedural heterogeneity was most pronounced for the parts not described in current guidelines, with choice of laboratory equipment being the most diverse factor ranging 3-39% nationally. In conclusion, the overall adherence to the national guidelines was high across regions, and obstetric departments and laboratories had high uniformity in the procedures for screening and diagnosing GDM. Uniformity was generally high for procedures included in the guideline and low if not included. However, a high proportion of GDM testing was performed outside the recommended gestational window in late pregnancy, which may be a pre-analytical contributor to regional differences in GDM prevalence.

Secular trend for increasing birthweight in offspring of pregnant women with type 1 diabetes: is improved placentation the reason?

Despite enormous progress in managing blood glucose levels, pregnancy in women with type 1 diabetes still carries risks for the growing fetus. While, previously, fetal undergrowth was not uncommon in these women, with improved maternal glycaemic control we now see an increased prevalence of fetal overgrowth. Besides short-term implications, offspring of women with type 1 diabetes are more likely to become obese and to develop diabetes and features of the metabolic syndrome. Here, we argue that the increase in birthweight is paradoxically related to improved glycaemic control in the pre- and periconceptional periods. Good glycaemic control reduces the prevalence of microangiopathy and improves placentation in early pregnancy, which may lead to unimpeded fetal nutrition. Even mild maternal hyperglycaemia may then later result in fetal overnutrition. This notion is supported by circumstantial evidence that lower HbA1c levels as well as increases in markers of placental size and function in early pregnancy are associated with large-for-gestational age neonates. We also emphasise that neonates with normal birthweight can have excessive fat deposition. This may occur when poor placentation leads to initial fetal undergrowth, followed by fetal overnutrition due to maternal hyperglycaemia. Thus, the complex interaction of glucose levels during different periods of pregnancy ultimately determines the risk of adiposity, which can occur in fetuses with both normal and elevated birthweight. Prevention of fetal adiposity calls for revised goal setting to enable pregnant women to maintain blood glucose levels that are closer to normal. This could be supported by continuous glucose monitoring throughout pregnancy and appropriate maternal gestational weight gain. Future research should consider the measurement of adiposity in neonates.

Prevalence and severity of diabetic retinopathy in pregnant women with diabetes-time to individualize photo screening frequency.

AIMS: To evaluate the prevalence and severity of diabetic retinopathy including macular oedema in pregnant women with diabetes and to identify women in whom the frequency of retinal screening can be reduced to minimize the burden of health care visits. METHODS: A cohort study of 348 women with pre-existing diabetes were routinely screened with retinal photo in early (12 weeks) and late pregnancy (27 weeks). Diabetic retinopathy was classified in five stages in accordance with National Danish Guidelines based on the eye with the highest retinopathy level. Sight-threatening retinopathy was defined as the presence of proliferative retinopathy and/or clinically significant macular oedema (CSMO). RESULTS: Retinopathy was present in 52% (116/223) vs. 14% (17/125), with sight-threatening retinopathy in 16% (35/223) vs. 6% (7/125) of women with type 1 and type 2, respectively. Women without retinopathy in early and late pregnancy were characterized by shorter diabetes duration (p < 0.0001 and p = 0.008) and predominance of type 2 diabetes. Amongst the 50% (175/348) of the cohort having no retinopathy in early pregnancy and HbA1c<53 mmol/mol (7.0%), none developed sight-threatening retinopathy and 94% (165/175) remained without any retinopathy during pregnancy. Development of sight-threatening retinopathy was mainly observed in women with retinopathy in early pregnancy. Treatment for sight-threatening retinopathy was given to a minority (2.7 and 2.4%, respectively). CONCLUSION: Good glycaemic control and no retinopathy was seen in a large proportion of women in early pregnancy and none of these women developed sight-threatening retinopathy. The frequency of retinal screening can probably be safely reduced during pregnancy in these women.

The impact of anti-hypertensive treatment on foetal growth and haemodynamics in pregnant women with pre-existing diabetes - An explorative study.

OBJECTIVES: To explore the impact of anti-hypertensive treatment of pregnancy-induced hypertension on foetal growth and hemodynamics in women with pre-existing diabetes. METHODS: A prospective cohort study of 247 consecutive pregnant women with pre-existing diabetes (152 type 1 diabetes; 95 type 2 diabetes), where tight anti-hypertensive treatment was initiated and intensified (mainly with methyldopa) when office blood pressure (BP) ≥135/85 mmHg and home BP ≥130/80 mmHg. Foetal growth was assessed by ultrasound at 27, 33 and 36 weeks and foetal hemodynamics were assessed by ultrasound Doppler before and 1-2 weeks after initiation of anti-hypertensive treatment. RESULTS: In 215 initially normotensive women, anti-hypertensive treatment for pregnancy-induced hypertensive disorders was initiated in 42 (20%), whilst 173 were left untreated. Chronic hypertension was present in 32 (13%). Anti-hypertensive treatment for pregnancy-induced hypertensive disorders was not associated with foetal growth deviation (linear mixed model, p = 0.681). At 27 weeks, mainly before initiation of anti-hypertensive treatment, the prevalence of small foetuses with an estimated foetal weight <10th percentile was 12% in women initiating anti-hypertensive treatment compared with 4% in untreated women (p = 0.054). These numbers were close to the prevalence of birth weight ≤10th percentile (small for gestational age (SGA)) (17% vs. 4%, p = 0.003). Pulsatility index in the umbilical and middle cerebral artery remained stable after the onset of anti-hypertensive treatment in a representative subgroup (n = 12, p = 0.941 and p = 0.799, respectively). CONCLUSION: There is no clear indication that antihypertensive treatment causes harm in this particular at-high-risk group of pregnant women with diabetes, such that a larger well-designed study to determine the value of tight antihypertensive control would be worthwhile.

Surgery in Patients with Gastro-Entero-Pancreatic Neuroendocrine Carcinomas, Neuroendocrine Tumors G3 and High Grade Mixed Neuroendocrine-Non-Neuroendocrine Neoplasms.

OPINION STATEMENT: In the 2019 WHO guidelines, the classification of gastro-entero-pancreatic neuroendocrine neoplasms (GEP NEN) has changed from one being based on Ki-67 proliferation index alone to one that also includes tumor differentiation. Consequently, GEP NENs are now classified as well-differentiated neuroendocrine tumor (NET), NET G1 (Ki-67 <3%), NET G2 (Ki-67 3-20%) and NET G3 (Ki-67 >20%), and poorly differentiated neuroendocrine carcinoma (NEC) (Ki-67 >20%). It has been suggested that NET G3 should be treated as NET G2 with respect to surgery, while surgical management of NEC should be expanded from local disease to also include patients with advanced disease where curative surgery is possible. High grade mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) have a neuroendocrine and a non-neuroendocrine component mostly with a poor prognosis. All studies evaluating the effect of surgery in NEC and MiNEN are observational and hold a risk of selection bias, which may overestimate the beneficial effect of surgery. Further, only a few studies on the effect of surgery in MiNEN exist. This review aims to summarize the data on the outcome of surgery in patients with GEP NET G3, GEP NEC and high grade MiNEN. The current evidence suggests that patients with NEN G3 and localized disease and NEN G3 patients with metastatic disease where curative surgery can be achieved may benefit from surgery. In patients with MiNEN, it is currently not possible to evaluate on the potential beneficial effect of surgery due to the low number of studies.

Potentially modifiable risk factors of preterm delivery in women with type 1 and type 2 diabetes.

AIMS/HYPOTHESIS: We aimed to identify potentially modifiable risk factors and causes for preterm delivery in women with type 1 or type 2 (pre-existing) diabetes. METHODS: A secondary analysis of a prospective cohort study of 203 women with pre-existing diabetes (117 type 1 and 86 type 2 diabetes) was performed. Consecutive singleton pregnancies were included at the first antenatal visit between September 2015 and February 2018. RESULTS: In total, 27% (n = 55) of the 203 women delivered preterm at median 36 + 0 weeks. When stratified by diabetes type, 33% of women with type 1 diabetes delivered preterm compared with 20% in women with type 2 diabetes (p = 0.04). Women delivering preterm were characterised by a higher prevalence of pre-existing kidney involvement (microalbuminuria or diabetic nephropathy) (16% vs 3%, p = 0.002), preeclampsia (26% vs 5%, p < 0.001), higher positive ultrasound estimated fetal weight deviation at 27 gestational weeks (2.7% vs -1.6% from the mean, p = 0.008), higher gestational weight gain (399 g/week vs 329 g/week, p = 0.01) and similar HbA1c levels in early pregnancy (51 mmol/mol [6.8%] vs 49 [6.6%], p = 0.22) when compared with women delivering at term. Independent risk factors for preterm delivery were pre-existing kidney involvement (OR 12.71 [95% CI 3.0, 53.79]), higher gestational weight gain (per 100 g/week, OR 1.25 [1.02, 1.54]), higher positive ultrasound estimated fetal weight deviation at 27 gestational weeks (% from the mean, OR 1.07 [1.03, 1.12]) and preeclampsia (OR 7.04 [2.34, 21.19]). Two-thirds of preterm deliveries were indicated and one-third were spontaneous. Several contributing factors to indicated preterm delivery were often present in each woman. The main indications were suspected fetal asphyxia (45%), hypertensive disorders (34%), fetal overgrowth (13%) and maternal indications (8%). Suspected fetal asphyxia mainly included falling insulin requirement and abnormal fetal haemodynamics. CONCLUSIONS/INTERPRETATIONS: Presence of preeclampsia, higher positive ultrasound estimated fetal weight deviation at 27 gestational weeks and higher gestational weight gain were independent potentially modifiable risk factors for preterm delivery in this cohort of women with pre-existing diabetes. Indicated preterm delivery was common with suspected fetal asphyxia or preeclampsia as the most prevalent causes. Prospective studies evaluating whether modifying these predictors will reduce the prevalence of preterm delivery are warranted.

Prevalence of anxiety and depression symptoms in pregnant women with type 2 diabetes and the impact on glycaemic control.

AIMS: To study the prevalence of anxiety and depression symptoms in pregnant women with type 2 diabetes compared with pregnant women without diabetes. Secondly, to explore whether anxiety and/or depression symptoms in early pregnancy have an impact on glycaemic control and gestational weight gain. METHODS: A prospective cohort study of 90 consecutive singleton pregnant women with type 2 diabetes and 88 singleton pregnant women without diabetes. All women completed the Hospital Anxiety and Depression Scale questionnaire in early and late pregnancy. A score ≥8 in the anxiety or the depression scale was used to define anxiety and/or depression symptoms. RESULTS: Anxiety and/or depression symptoms were present in 40% of women with type 2 diabetes and 7% of women without diabetes in early pregnancy (Relative Risk = 5.87 (95% Confidence Interval: 2.60-13.22)). The figures were similar in late pregnancy. In women with type 2 diabetes and anxiety and/or depression symptoms in early pregnancy, HbA1c (mean ± SD) was 52 ± 14 vs. 49 ± 11 mmol/mol (6.9 ± 1.2 vs. 6.6 ± 1.0%), p = 0.31 in early pregnancy and 43 ± 8 vs. 40 ± 4 mmol/mol (6.1 ± 0.7 vs. 5.8 ± 0.4%), p = 0.04 in late pregnancy compared with women without symptoms. Gestational weight gain was similar in both groups. CONCLUSIONS: In women with type 2 diabetes, 40% had anxiety and/or depression symptoms in early pregnancy. Women with these symptoms obtained less optimal glycaemic control in late pregnancy but similar gestational weight gain as the remaining women.

Diabetes Management During Breastfeeding in Women with Type 1 Diabetes.

PURPOSE OF REVIEW: To provide an update on glycemic management of type 1 diabetes during breastfeeding with focus on diet and insulin treatment to prevent hypoglycemia, ketoacidosis, and weight retention. Recommendations for insulin pump settings are given. RECENT FINDINGS: Women with type 1 diabetes are encouraged to breastfeed. Hypoglycemia is a concern in the breastfeeding period among women with type 1 diabetes, and ketoacidosis may also occur. The usual goals for glucose values for persons with diabetes also apply during breastfeeding. The recommended minimum daily carbohydrate intake is 210 g during breastfeeding, and this may contribute to prevention of hypoglycemia and ketoacidosis while aiming for gradual weight loss. Insulin requirements are 21% lower during breastfeeding than before pregnancy. Diabetes management in breastfeeding women with type 1 diabetes includes the same goals for glucose values as in other persons with diabetes, sufficient carbohydrate intake, and adequate reduction in insulin dose.

White coat hypertension in early pregnancy in women with pre-existing diabetes: prevalence and pregnancy outcomes.

AIMS/HYPOTHESIS: Hypertensive disorders are prevalent among pregnant women with pre-existing diabetes, but the prevalence and impact of white coat hypertension are unknown. Measurement of home BP before initiation of antihypertensive treatment is necessary to identify white coat hypertension since international guidelines recommend that white coat hypertension is left untreated. The aim of this study, conducted among women with pre-existing diabetes, was therefore to examine the prevalence of white coat hypertension in early pregnancy, and pregnancy outcome in women with white coat hypertension in early pregnancy. METHODS: A prospective cohort study was undertaken involving women with pre-existing diabetes from a geographically well-defined area. Based on office BP in early pregnancy and home BP measured for 3 days, women were categorised in three groups: (1) white coat hypertension, defined as office BP ≥ 135/85 mmHg and mean home BP < 130/80 mmHg; (2) chronic hypertension, defined as pre-pregnancy hypertension including newly detected office BP ≥ 135/85 mmHg with home BP ≥ 130/80 mmHg; and (3) normotension. Office BP was measured every 2 weeks and, if ≥ 135/85 mmHg, home BP measurements were performed. White coat hypertension was left untreated, and tight antihypertensive treatment was initiated when both office BP ≥ 135/85 mmHg and home BP ≥ 130/80 mmHg. Pregnancy-induced hypertensive disorders were defined as office BP ≥ 140/90 mmHg with home BP ≥ 130/80 mmHg when available, with onset after 20 weeks of gestation. RESULTS: In total, 32 out of 222 women with pre-existing diabetes had newly detected office BP ≥ 135/85 mmHg in early pregnancy. White coat hypertension was present in 84% (27/32) of these women, representing 12% (95% CI 8%, 17%) of the whole cohort. Chronic hypertension was present in 14% (n = 32) and normotension in 74% (n = 163). Women with white coat hypertension were characterised by higher pre-pregnancy BMI (p = 0.011), higher home BP (p < 0.001) and higher prevalence of type 2 diabetes (p = 0.009), but similar HbA1c (p = 0.409) compared to women with normotension. Regarding pregnancy outcome, pregnancy-induced hypertensive disorders developed in 44% (12/27) of women with white coat hypertension in comparison with 22% (36/163) among initially normotensive women (p = 0.013), while the prevalence of preterm delivery was comparable (p = 0.143). The adjusted analysis, performed post hoc, suggested approximately double the risk of developing pregnancy-induced hypertensive disorders (OR 2.43 [CI 0.98, 6.05]) if white coat hypertension was present in early pregnancy, independently of pre-pregnancy BMI and parity. CONCLUSIONS/INTERPRETATION: White coat hypertension is prevalent in women with pre-existing diabetes and may indicate a high risk of later development of pregnancy-induced hypertensive disorders. To distinguish between persistent white coat hypertension and onset of pregnancy-induced hypertension, repeated home BP monitoring is recommended when elevated office BP is detected. The study was registered at ClinicalTrials.gov (ID: NCT02890836).

Breastfeeding at night is rarely followed by hypoglycaemia in women with type 1 diabetes using carbohydrate counting and flexible insulin therapy.

AIMS/HYPOTHESIS: Hypoglycaemia in association with breastfeeding is a feared condition in mothers with type 1 diabetes. Thus, routine carbohydrate intake at each breastfeed, particularly at night, is often recommended despite lack of evidence. We aimed to evaluate glucose levels during breastfeeding, focusing on whether night-time breastfeeding induced hypoglycaemia in mothers with type 1 diabetes. METHODS: Of 43 consecutive mothers with type 1 diabetes, 33 (77%) were included prospectively 1 month after a singleton delivery. Twenty-six mothers (mean [SD] age 30.7 [5.8] years, mean [SD] duration of diabetes 18.6 [10.3] years) were breastfeeding and seven mothers (mean [SD] age 31.7 [5.6] years, mean [SD] duration of diabetes 20.4 [6.2] years) were bottle-feeding their infants with formula. All were experienced in carbohydrate counting using individually tailored insulin therapy with insulin analogues (45% on insulin pump, 55% on multiple daily injections). Thirty-two women with type 1 diabetes, matched for age ±1 year and BMI ±1 kg/m2, who had not given birth or breastfed in the previous year, served as a control group. Blinded continuous glucose monitoring (CGM) for 6 days was applied at 1, 2 and 6 months postpartum in the breastfeeding mothers who recorded breastfeeds and carbohydrate intake at each CGM period. CGM was applied at 1 month postpartum in the formula-feeding mothers and once in the control women. The insulin dose was individually tailored after each CGM period. RESULTS: The percentage of night-time spent with CGM <4.0 mmol/l was low (4.6%, 3.1% and 2.7% at each CGM period in the breastfeeding mothers vs 1.6% in the control women, p = 0.77), and the breastfeeding mothers spent a greater proportion of the night-time in the target range of 4.0-10.0 mmol/l (p = 0.01). Symptomatic hypoglycaemia occurred two or three times per week at 1, 2 and 6 months postpartum in both breastfeeding mothers and the control women. Severe hypoglycaemia was reported by one mother (3%) during the 6 month postpartum period and by one control woman (3%) in the previous year (p = 0.74). In breastfeeding mothers at 1 month, the insulin dose was 18% (-67% to +48%) lower than before pregnancy (p = 0.04). In total, carbohydrate was not consumed in relation to 438 recorded night-time breastfeeds, and CGM <4.0 mmol/l within 3 h occurred after 20 (4.6%) of these breastfeeds. CONCLUSIONS/INTERPRETATION: The percentage of night-time spent in hypoglycaemia was low in the breastfeeding mothers with type 1 diabetes and was similar in the control women. Breastfeeding at night-time rarely induced hypoglycaemia. The historical recommendation of routine carbohydrate intake at night-time breastfeeding may be obsolete in mothers with type 1 diabetes who have properly reduced insulin dose with sufficient carbohydrate intake. TRIAL REGISTRATION: ClinicalTrials.gov NCT02898428.

Vitamin D insufficiency, preterm delivery and preeclampsia in women with type 1 diabetes - an observational study.

INTRODUCTION: The aim of this study was to evaluate whether vitamin D insufficiency is associated with preterm delivery and preeclampsia in women with type 1 diabetes. MATERIAL AND METHODS: An observational study of 198 pregnant women with type 1 diabetes. 25-Hydroxy-Vitamin D and HbA1c were measured in blood samples in early (median 8 weeks, range 5-14) and late (34 weeks, range 32-36) pregnancy. Kidney involvement (microalbuminuria or nephropathy) at inclusion, smoking status at inclusion, preterm delivery (<37 weeks) and preeclampsia (blood pressure ≥140/90 mmHg and proteinuria) were registered. Vitamin D supplementation of 10 µg daily was routinely recommended. RESULTS: Thirty-nine (20%) of the 198 women delivered preterm and 16 (8%) developed preeclampsia. Vitamin D insufficiency (<50 nmol/L) was present in 68 women (34%) in early pregnancy and in 73 women (37%) in late pregnancy. Preterm delivery occurred more frequently in women with vitamin D insufficiency in late pregnancy (27% vs. 15%, crude odds ratio 2.1; 95% confidence interval 1.0-4.3, p = 0.04). After adjustment for preexisting kidney involvement, HbA1c in late pregnancy and smoking the association became nonsignificant (adjusted odds ratio 1.8; 95% confidence interval 0.8-3.7). Preeclampsia developed in 11% of women with vitamin D insufficiency vs. 6% of the remaining women (crude odds ratio 1.8; 95% confidence interval 0.9-4.1, p = 0.25). CONCLUSION: In women with type 1 diabetes, preterm delivery was twice as frequent in women with vitamin D insufficiency in late pregnancy in crude analysis, but in this small study, low vitamin D was not independently associated with preterm birth or preeclampsia.

Quality of life, anxiety and depression symptoms in early and late pregnancy in women with pregestational diabetes.

INTRODUCTION: The aim of this study was to explore changes in health-related quality of life, anxiety and depression symptoms during pregnancy in women with pregestational diabetes. MATERIAL AND METHODS: An observational cohort study including 137 pregnant women with pregestational diabetes (110 with type 1 and 27 with type 2). To evaluate changes from early to late pregnancy, the internationally validated questionnaires 36-Item Short-Form Health Survey (SF-36) and Hospital Anxiety and Depression Scale (HADS) were completed at 8 and 33 gestational weeks. RESULTS: From early to late pregnancy, the SF-36 scales Physical Function, Role Physical, Bodily Pain and Physical Component Summary worsened (p < 0.0001 for all scales). Physical Component Summary score deteriorated from mean 52.3 (SD 6.5) to 40.0 (9.7) (p < 0.0001) and the deterioration was negatively associated with gestational weight gain in multiple linear regression (ß = -0.34/kg, p = 0.03). The SF-36 scale Mental Health improved (p = 0.0009) and the Mental Component Summary score increased moderately from 47.6 (10.6) to 53.5 (8.6) (p < 0.0001). Greater improvement in Mental Component Summary score was seen with lower HbA1c in late pregnancy. The HADS anxiety score improved slightly from 5.0 (3.3) to 4.5 (3.4) (p = 0.04) whereas the HADS depression score remained unchanged. The prevalence of women with HADS anxiety or depression score ≥8 did not change. CONCLUSIONS: Physical quality of life deteriorated whereas mental quality of life improved slightly during pregnancy in women with pregestational diabetes. A minor reduction in anxiety and stable depression symptoms was observed. The results on mental health are reassuring, considering the great demands that pregnancy places on women with pregestational diabetes.

Diabetic Nephropathy in Women With Preexisting Diabetes: From Pregnancy Planning to Breastfeeding.

In women with preexisting diabetes and nephropathy or microalbuminuria, it is important to deliver careful preconception counselling to assess the risk for the mother and the foetus, for optimizing glycaemic status and to adjust medical treatment. If serum creatinine is normal in early pregnancy, kidney function is often preserved during pregnancy, but complications such as severe preeclampsia and preterm delivery are still common. Perinatal mortality is now comparable with that in women with diabetes and normal kidney function. Besides strict glycaemic control before and during pregnancy, early and intensive antihypertensive treatment is important to optimize pregnancy outcomes. Methyldopa, labetalol, nifedipine and diltiazem are considered safe, whereas angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers should be stopped before or at confirmation of pregnancy. Supplementation with folic acid in early pregnancy and low-dose aspirin from 10 to 12 weeks reduces the risk of adverse pregnancy outcomes. During breastfeeding, several ACE inhibitors are considered safe.

Implications for the offspring of circulating factors involved in beta cell adaptation in pregnancy.

OBJECTIVE: Several studies have shown an increase in beta cell mass during pregnancy. Somatolactogenic hormones are known to stimulate the proliferation of existing beta cells in rodents whereas the mechanism in humans is still unclear. We hypothesize that in addition to somatolactogenic hormones there are other circulating factors involved in beta cell adaptation to pregnancy. This study aimed at screening for potential pregnancy-associated circulating beta cell growth factors. SAMPLES: Serum samples from nonpregnant and pregnant women. METHODS: The effect of serum from pregnant women on the proliferation of rat beta cells was studied using [3H]thymidine incorporation and 5-ethynyl-2'-deoxyuridine proliferation assays. In addition, serum from pregnant and nonpregnant women was fractionated by gel filtration and high performance liquid chromatography. The fractionated serum was screened for mitogenic activity in INS-1E cells. Proteins and peptides in mitogenic active serum fractions were identified by amino acid sequencing and mass spectrometry. MAIN OUTCOME MEASURES: Presence of circulating beta cell proliferating factors. RESULTS: Late gestational pregnancy serum significantly increased proliferation of rat beta cells compared with early pregnancy and nonpregnancy. The mitogenic active serum fractions contained proteins and peptides derived from kininogen-1, fibrinogen-α, α1-antitrypsin, apolipoprotein-A1, placental lactogen, angiotensinogen and serum albumin. CONCLUSION: Pregnancy serum is able to stimulate proliferation of rat beta cells. We have identified several circulating factors that may contribute to beta cell adaptation to pregnancy. Further studies are needed to elucidate their possible role in glucose homeostasis in the mother and her offspring.

Automated Insulin Delivery for Pregnant Women With Type 1 Diabetes: Where do we stand?

Automated insulin delivery (AID) systems mimic an artificial pancreas via a predictive algorithm integrated with continuous glucose monitoring (CGM) and an insulin pump, thereby providing AID. Outside of pregnancy, AID has led to a paradigm shift in the management of people with type 1 diabetes (T1D), leading to improvements in glycemic control with lower risk for hypoglycemia and improved quality of life. As the use of AID in clinical practice is increasing, the number of women of reproductive age becoming pregnant while using AID is also expected to increase. The requirement for lower glucose targets than outside of pregnancy and for frequent adjustments of insulin doses during pregnancy may impact the effectiveness and safety of AID when using algorithms for non-pregnant populations with T1D. Currently, the CamAPS® FX is the only AID approved for use in pregnancy. A recent randomized controlled trial (RCT) with CamAPS® FX demonstrated a 10% increase in time in range in a pregnant population with T1D and a baseline glycated hemoglobin (HbA1c) ≥ 48 mmol/mol (6.5%). Off-label use of AID not approved for pregnancy are currently also being evaluated in ongoing RCTs. More evidence is needed on the impact of AID on maternal and neonatal outcomes. We review the current evidence on the use of AID in pregnancy and provide an overview of the completed and ongoing RCTs evaluating AID in pregnancy. In addition, we discuss the advantages and challenges of the use of current AID in pregnancy and future directions for research.

Mean Glucose and Gestational Weight Gain as Predictors of Large-for-Gestational-Age Infants in Pregnant Women with Type 1 Diabetes Using Continuous Glucose Monitoring.

Aims/hypothesis: To compare glycemic metrics during pregnancy between women with type 1 diabetes (T1D) delivering large-for-gestational-age (LGA) and appropriate-for-gestational-age (AGA) infants, and to identify predictors of LGA infants. Materials and Methods: A cohort study including 111 women with T1D using intermittently scanned continuous glucose monitoring from conception until delivery. Average sensor-derived metrics: mean glucose, time in range in pregnancy (TIRp), time above range in pregnancy, time below range in pregnancy, and coefficient of variation throughout pregnancy and in pregnancy intervals of 0-10, 11-21, 22-33, and 34-37 weeks were compared between women delivering LGA and AGA infants. Predictors of LGA infants were sought for. Infant growth was followed until 3 months postdelivery. Results: In total, 53% (n = 59) delivered LGA infants. Mean glucose decreased during pregnancy in both groups, with women delivering LGA infants having a 0.4 mmol/L higher mean glucose from 11-33 weeks (P = 0.01) compared with women delivering AGA infants. Mean TIRp >70% was obtained from 34 weeks in women delivering LGA infants and from 22-33 weeks in women delivering AGA infants. Independent predictors for delivering LGA infants were mean glucose throughout pregnancy and gestational weight gain. At 3 months postdelivery, infant weight was higher in infants born LGA compared with infants born AGA (6360 g ± 784 and 5988 ± 894, P = 0.04). Conclusions/interpretations: Women with T1D delivering LGA infants achieved glycemic targets later than women delivering AGA infants. Mean glucose and gestational weight gain were independent predictors for delivering LGA infants. Infants born LGA remained larger postdelivery compared with infants born AGA.

Danish Diabetes Birth Registry 2: a study protocol of a national prospective cohort study to monitor outcomes of pregnancies of women with pre-existing diabetes.

INTRODUCTION: Despite technological developments and intensified care, pregnancies in women with pre-existing diabetes are still considered high-risk pregnancies. The rate of adverse outcomes in pregnancies affected by diabetes in Denmark is currently unknown, and there is a limited understanding of mechanisms contributing to this elevated risk. To address these gaps, the Danish Diabetes Birth Registry 2 (DDBR2) was established. The aims of this registry are to evaluate maternal and fetal-neonatal outcomes based on 5 years cohort data, and to identify pathophysiology and risk factors associated with short-term and long-term outcomes of pregnancies in women with pre-existing diabetes. METHODS AND ANALYSIS: The DDBR2 registry is a nationwide 5-year prospective cohort with an inclusion period from February 2023 to February 2028 of pregnancies in women with all types of pre-existing diabetes and includes registry, clinical and questionnaire data and biological samples of mother-partner-child trios. Eligible families (parents age ≥18 years and sufficient proficiency in Danish or English) can participate by either (1) basic level data obtained from medical records (mother and child) and questionnaires (partner) or (2) basic level data and additional data which includes questionnaires (mother and partner) and blood samples (all). The primary maternal outcome is Hemoglobin A1c (HbA1c) levels at the end of pregnancy and the primary offspring endpoint is the birth weight SD score. The DDBR2 registry will be complemented by genetic, epigenetic and metabolomic data as well as a biobank for future research, and the cohort will be followed through data from national databases to illuminate possible mechanisms that link maternal diabetes and other parental factors to a possible increased risk of adverse long-term child outcomes. ETHICS AND DISSEMINATION: Approval from the Ethical Committee is obtained (S-20220039). Findings will be sought published in international scientific journals and shared among the participating hospitals and policymakers. TRIAL REGISTRATION NUMBER: NCT05678543.

Impaired hormonal counterregulation to biochemical hypoglycaemia does not explain the high incidence of severe hypoglycaemia during pregnancy in women with type 1 diabetes.

AIMS: To explore hormonal counterregulation to biochemical hypoglycaemia during pregnancy. METHODS: Observational study of 107 consecutive pregnant women with type 1 diabetes (median duration 16 years (range 1-36), HbA1c 6.6% (4.9-10.5) in early pregnancy) and 22 healthy pregnant women. At 8, 14, 21, 27 and 33 weeks (women with diabetes) and 15, 28 and 34 weeks (healthy women) blood was sampled for measurements of glucose, adrenaline, noradrenaline, cortisol and glucagon. Each woman's measurement of serum glucose was matched with her corresponding hormone concentrations. Severe hypoglycaemia (requiring help from another person) was recorded prospectively. RESULTS: During normoglycaemia (serum glucose > 3.9 mmol/L), adrenaline concentrations were higher in early pregnancy compared with late pregnancy in women with diabetes (21 (7-111) pg/ml vs. 17 (2-131), p = 0.02) and healthy women (21 (10-37) pg/ml vs. 13 (5-49), p = 0.046). Biochemical hypoglycaemia (serum glucose ≤ 3.9 mmol/L) occurred in 70 women with diabetes (65%) in at least one of the five samplings. At 8 and 33 weeks, adrenaline concentrations at biochemical hypoglycaemia were similar (30 (5-164) pg/ml and 29 (9-152), p = 0.79). Adrenaline concentrations at biochemical hypoglycaemia increased from normoglycaemia at diabetes duration < 16 years (p = 0.03). In first trimester, adrenaline concentrations were comparable in women with or without severe hypoglycaemia (24 (14-164) pg/ml vs. 33 (5-86), p = 0.35). Noradrenaline, glucagon and cortisol concentrations did not increase during biochemical hypoglycaemia. CONCLUSION: Adrenaline response to biochemical hypoglycaemia was present at similar levels in early and late pregnancy, particularly in shorter diabetes duration, and was not associated with severe hypoglycaemia in early pregnancy.

Major congenital malformations in offspring of women with chronic diseases-impact of the disease or the treatment?

In a narrative review, we summarized previous findings on the risk of major congenital malformations in offspring of women with chronic hypertension, hypothyroidism, or depression compared with the background population, and evaluated whether exposure to medical treatment in the first trimester affected this risk. In a literature search in the PubMed database, cohort studies were included if they were published from 2010 to 2022 and contained data on major congenital malformations from ≥500 offspring of women with chronic hypertension, hypothyroidism, or depression during the first trimester of pregnancy, and data on both untreated and treated women. Data were compared with the background population of women without these diseases. In total, 7 cohort studies were identified. In comparison with the background population, 2 studies including 54,996 offspring of women with chronic hypertension showed an adjusted odds ratio of 1.20 to 1.30 for major congenital malformations in the offspring, regardless of antihypertensive treatment. One study including 16,364 offspring of women with hypothyroidism showed an adjusted odds ratio of 1.14 (1.06-1.22) for major congenital malformations in the offspring, regardless of thyroid substitution. Four studies including 48,913 offspring of women with depression showed adjusted odds ratios of 1.07 to 1.27 (0.91-1.78) for major congenital malformations in the offspring of untreated women. Three of these 4 studies showed similar prevalence of malformations in women treated for depression. The findings of this narrative review suggest that chronic hypertension and hypothyroidism, rather than exposure to their medical treatments in the first trimester, were associated with increased risk of major congenital malformations, whereas depression was generally not associated with major congenital malformations.