OBJECTIVE:To examine the associations between continuous glucose monitoring (CGM) metrics, including glucose management indicator (GMI) and overnight glucose levels, and pregnancy outcomes in women with type 1 diabetes. RESEARCH DESIGN AND METHODS:Secondary exploratory analysis of the CRISTAL trial including 95 pregnant women with type 1 diabetes using CGM. Associations were assessed using logistic regression and Spearman correlations, presented as odds ratios (95% confidence intervals [CIs]) adjusted for baseline HbA1c. GMI validity was assessed using scatter and Bland-Altman plots. RESULTS:Each 5% increase in overall pregnancy-specific time-in-range (TIRp) decreased the odds of gestational hypertension (odds ratio [OR] 0.63, 95% CI 0.41-0.97), birthweight >4.5 kg (OR 0.56, 95% CI 0.32-0.96), and neonatal hypoglycemia requiring hospital care (OR 0.09, 95% CI 0.01-0.57). Each 5% increase in overnight TIRp decreased the odds of gestational hypertension (OR 0.71, 95% CI 0.52-0.98) and neonatal hypoglycemia requiring hospital care (OR 0.15, 95% CI 0.03-0.79). Each 5% increase in overall time-above-range (TARp) increased the odds of birthweight >4.5 kg (OR 1.76, 95% CI 1.05-2.96), respiratory distress (OR 1.55, 95% CI 1.02-2.37), and neonatal hypoglycemia requiring hospital care (OR 5.10, 95% CI 1.14-22.78). Each 5% increase in TARp overnight increased the odds of hospital care for neonatal hypoglycemia (OR 2.55, 95% CI 1.15-5.66). Each 0.28 mmol/L increase in mean glucose and 0.5% increase in GMI were associated with increased respiratory distress (OR 1.54, 95% CI 1.07-2.23 and OR 6.15, 95% CI 1.33-28.40). Every 0.28 mmol/L increase in glycemic variability (SD) was associated with gestational hypertension (OR 1.69, 95% CI 1.02-2.80) and birthweight >4.5 kg (OR 2.31, 95% CI 1.20-4.43). Several combinations of CGM metrics (TIRp[-night], TARp[-night], SD, mean glucose) improved discriminative performance for pregnancy outcomes. GMI and HbA1c values were discordant. CONCLUSIONS:Specific combinations of CGM metrics, including overnight TIRp/TARp, may be informative for predicting pregnancy outcomes. GMI and HbA1c should not be considered interchangeable for glycemic control during pregnancy.

OBJECTIVE:The CRISTAL trial indicated that advanced hybrid closed loop (AHCL) therapy with MiniMed™ 780G in type 1 diabetes pregnancy did not improve time in range (TIRp) compared with standard insulin therapy (SoC), but improved TIRp overnight and reduced time below range (TBRp). We aimed to evaluate the effect of AHCL therapy across different subgroups. RESEARCH DESIGN AND METHODS:This secondary analysis of the CRISTAL randomized controlled trial compared glycemic outcomes (TIRp, TIRp overnight, TBRp, and TBRp overnight) averaged over the antenatal period (14-, 20-, 26-, and 33-weeks' gestation) between the AHCL and SoC groups, within subgroups defined by baseline characteristics. RESULTS:In women with baseline HbA1c <7.0%, the AHCL group (n = 35) had a significantly higher TIRp than SoC (n = 37), with a mean difference of 5.64% (95% confidence interval [95% CI]: 1.32-9.96), corresponding to 1 h 21 min more TIRp per day and 11.89% (95% CI: 7.01-16.76) higher TIRp overnight. In women without prior AHCL use, TIRp was 6.29% higher (95% CI: 0.90-11.68) and overnight TIRp 11.91% higher (95% CI: 5.65-18.16) in the AHCL group (n = 24) compared with SoC (n = 28). In women without higher education, AHCL users (n = 14) had a significantly higher TIRp compared with SoC (n = 14) with a difference of 7.33% (95% CI: 0.88-13.78). TBRp was significantly lower in AHCL users with baseline HbA1c <7.0% and in women without prior AHCL use. CONCLUSIONS:AHCL therapy improved glycemic management in pregnant women with baseline HbA1c <7.0%, in women without prior AHCL use, and in women without higher education, indicating that AHCL might particularly benefit these subgroups.

In type 1 diabetes, optimal glucose management during the peripartum period is critical to reduce neonatal hypoglycemia shortly after birth as well as maternal hypoglycemia postpartum when insulin requirements fall quickly. Healthcare professionals and their patients must consider the mode of insulin delivery during the peripartum period, meaning either to keep a person's own subcutaneous insulin delivery mode- including automated insulin delivery (AID) systems - or to switch to an intravenous insulin/glucose infusion. In this article, we review continuation of AID systems during the peripartum period in women with type 1 diabetes. We included data from local and (inter)national guidelines, evidence from recent publications, and combined this with data from our own clinic. We recommend continuing an AID system over switching to manual mode or an insulin/glucose infusion, provided this is preferred by the patient and several basic criteria are fulfilled.

Outcome reporting in hyperemesis gravidarum (HG) research lacks standardization, which hampers the aggregation of data. A core outcome set (COS) for HG research has been developed to increase standardization. While a COS represents which key outcomes should be measured, it does not describe how and when they should be measured. Our aim was to develop a consensus-based core outcome measurement set for HG complementing the existing COS for HG. This study included multiple phases: (1) systematic review to identify all existing outcome measurement instrument (OMI)s in HG research; (2) a consensus meeting with the steering committee of this study to vote for one best OMI per outcome; (3) a modified Delphi consultation survey of at least 100 stakeholders including patients, obstetric healthcare professionals, other healthcare professionals and researchers to achieve consensus on one OMI per outcome. The literature review identified 362 unique OMIs in 461 studies. The modified Delphi consultation round included 155 stakeholders including researchers (12.3

BACKGROUND:Hyperemesis gravidarum, a condition characterized by severe nausea and vomiting in pregnancy, is now understood to be partly attributable to high placentally derived growth differentiation factor 15 concentrations, which increase rapidly from early pregnancy. Intriguingly, accumulating evidence has suggested that low preconception growth differentiation factor 15 concentrations predispose to hyperemesis gravidarum, suggesting that growth differentiation factor 15 preconditioning may offer a modifiable factor, which could be harnessed as the first preventive strategy for hyperemesis gravidarum. Metformin, a drug that is safe and widely used in pregnancy, increases the growth differentiation factor 15 level. OBJECTIVE:This study aimed to determine whether and at what duration and timing of preconception metformin use might lower the prevalence or recurrence of hyperemesis gravidarum. STUDY DESIGN:This was a population-based registry study of all pregnancies with a gestational age of ≥10 weeks between 1998 and 2018 in Denmark. Metformin use was estimated by the redemption of metformin prescription before pregnancy. The main outcome was the prevalence of hyperemesis gravidarum based on the International Classification of Diseases codes. RESULTS:In 1,447,968 pregnancies, 1.9% had a hyperemesis gravidarum diagnosis, with a recurrence rate of 26.0%. Preconception metformin use did not decrease hyperemesis gravidarum prevalence (1.9%) or recurrence (27%). However, preconception metformin use continued for ≥6 months was associated with a lower prevalence of hyperemesis gravidarum of 1.1% (adjusted odds ratio, 0.49 [95% confidence interval, 0.31-0.75]) than preconception metformin use for <2 months. If metformin was continued up to conception (last redemption within the first month after conception), the prevalence of hyperemesis gravidarum was 1.2% (adjusted odds ratio, 0.61 [95% confidence interval, 0.38-0.95]), compared with the discontinuation of metformin longer before conception. The effect remained after correcting for metformin indication and other potential confounders. CONCLUSION:Our findings suggest that metformin in preconception, with 6-month usage and continued usage up to 1 month after conception, may present the first preventive strategy for patients at high risk of hyperemesis gravidarum. Owing to the observational nature of our study, randomized trials need to further investigate the utility of this strategy.

Importance Pregnant individuals with polycystic ovary syndrome (PCOS) present with a higher risk of pregnancy complications, including gestational diabetes, preeclampsia, and preterm birth. Myo-inositol supplementation may reduce these risks. Objective To determine whether daily supplementation with myo-inositol during pregnancy among individuals with PCOS reduces the risk of a composite outcome of gestational diabetes, preeclampsia, and preterm birth. Design, Setting, and Participants This double-blind, placebo-controlled, randomized trial was conducted at 13 hospitals in the Netherlands. Pregnant individuals with PCOS who were between 8 and 16 weeks' gestation were enrolled between June 2019 and March 2023. Final follow-up was complete on December 27, 2023. Analyses were conducted July 2024. Interventions Participants were randomized on a 1:1 basis to receive sachets with either myo-inositol, 2 g, with 0.2 mg of folic acid twice daily (n = 230) or matching placebo with 0.2 mg of folic acid only (n = 234) until delivery. Main Outcomes and Measures The primary outcome was a composite of gestational diabetes, preeclampsia, or preterm birth (before 37 weeks' gestation). Results Among 464 participants, the mean (SD) age was 31.5 (3.8) years; 18 participants (3.9%) reported Asian race and 395 (86.1%) reported White race. The prevalence of biochemical hyperandrogenism was higher at baseline in the myo-inositol group than the placebo group (29.0% [53 of 180] vs 18.5% [37 of 193]). A primary outcome event occurred in 25.0% (n = 56) of participants in the myo-inositol group and 26.8% (n = 61) in the placebo group (relative risk, 0.93 [95% CI, 0.68-1.28]; P = .67). Conclusions and Relevance Myo-inositol supplementation during pregnancy did not reduce the incidence of a composite of gestational diabetes, preeclampsia, or preterm birth in patients with PCOS.

Diabetes is among the most prevalent chronic diseases worldwide, with incidence rising each year, shaped by social inequities which influence both vulnerability to disease and access to quality care. These inequities and their systemic drivers are collectively termed the Social Determinants of Health (SDOH). Pregnancy introduces additional physiological and social challenges that can intensify existing inequities. For individuals with diabetes, pregnancy can compound adverse SDOH, increasing both risks and disparities in perinatal outcomes. To effectively manage pregestational diabetes, healthcare professionals must expand their clinical knowledge to understand impact of SDOH, and systematically screen and refer to relevant social support programs. The root causes of SDOH lie in the systems and policies; engaging in advocacy is only way to enact systemic change and complements any individual-level efforts. This review aims to improve adverse perinatal outcomes by providing practical clinical tools to address SDOH in pregestational diabetes in European context.

Background Hyperemesis Gravidarum (HG), severe nausea and vomiting in pregnancy (NVP), is now understood to be partly attributable to high placentally derived Growth Differentiation Factor (GDF)-15 concentrations, which rise rapidly from early pregnancy. Intriguingly, accumulating evidence has suggested that low preconception GDF-15 concentrations predispose to HG, suggesting that GDF-15 preconditioning may offer a modifiable factor, which could be harnessed as the first preventive strategy for HG. Metformin, a drug that is safe and widely used in pregnancy, increases GDF-15. Objective Here, we aimed to determine whether, and at which duration and timing of use, preconception metformin might lower the prevalence or recurrence of HG. Study Design A population-based registry study of all pregnancies with a gestational age ≥ 10 weeks between 1998 and 2018 in Denmark. Metformin use was estimated by redemption of metformin prescription prior to pregnancy. Main outcome was prevalence of HG based on ICD codes. Results In 1,447,968 pregnancies, 1.9% had a HG diagnosis with a recurrence rate of 26%. Preconception use of metformin did not decrease HG prevalence (1.9%) or recurrence rate (27%). %). However, preconception metformin use continued for ≥6 months was associated with a lower prevalence of HG of 1.1% (adjusted OR 0.49; 95% CI 0.31-0.75), compared to < 2 months of use. If metformin was continued up to conception (last redemption within the first month post-conception), the prevalence of HG was 1.2% (adjusted OR 0.61; 95% CI 0.38-0.95) compared to discontinuation longer before conception. The effect remained after correcting for metformin indication and other potential confounders. Conclusion Our findings suggest that metformin in preconception, with 6-month usage and continued usage up to 1-month post-conception, may present the first-preventive strategy for those at high risk of HG. Due to the observational nature of our study, randomized trials need to further investigate the utility of this strategy.

Background A multicentre, randomised controlled trial (the CRISTAL trial), demonstrated the safety and efficacy of MiniMedTM 780G advanced hybrid closed loop (AHCL) therapy during pregnancy, showing improved glycaemic control overnight, less hypoglycaemia, and improved treatment satisfaction compared to standard insulin therapy (SoC, mainly open-loop insulin pump therapy). This study aimed to assess the cost-effectiveness of AHCL, which has a higher initial cost, compared to SoC in pregnant women with type 1 diabetes (T1D). Methods A decision tree model was developed to estimate the cost-effectiveness of AHCL compared to SoC in pregnant women with T1D, covering pregnancy to birth and postpartum hospital discharge (a time horizon of 28 weeks). Total costs per strategy (in 2024 euros, ) were calculated from a healthcare payer perspective. The base- case analysis derived prevalence of pregnancy complications and hospitalisations directly related to diabetes management from the CRISTAL trial. Uncertainty was analysed by exploring multiple scenarios and sensitivity analyses. Findings In the base-case analysis, the cost of using AHCL during pregnancy was estimated at 13,988.75 (95% CI: 12,240 to 16,062) compared to 14,221.33 (95% CI: 12,380 to 16,420) for SoC, indicating cost-savings of 232.57 per individual, alongside the demonstrated clinical benefits of AHCL. The primary cost driver was the AHCL device cost. This cost was offset by savings from shorter and less frequent hospital admissions (mainly due to severe hypoglycaemia and dysregulated diabetes) in the AHCL group compared to SoC. In our probabilistic sensitivity analysis, AHCL was dominant in 73% of the simulated cost-effectiveness pairs. Interpretation AHCL might be cost-saving compared to SoC for pregnant women with T1D. However, more robust data are needed to assess the potential impact of AHCL therapy on pregnancy and long-term health outcomes. Copyright (c) 2025 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Pregnant women with polycystic ovary syndrome (PCOS) have an increased risk of gestational diabetes mellitus (GDM), preeclampsia and preterm birth, and their offspring are more likely to have an abnormal birth weight and require hospitalization. Current preventive strategies to reduce the rate of pregnancy complications associated with PCOS have ineffective. Myo-inositol supplementation has shown promising clinical benefit in preventing adverse outcomes in individuals with obesity and PCOS-related disorders. Recent randomized controlled trials using daily supplementation with 4 grams of myo-inositol during pregnancy estimated a relative reduction of up to 65% for GDM and preterm delivery.(1-7) These studies included both obese patients and patients with normal body weight. From these trials, post-hoc analysis suggested similar, or even greater, reductions in the sub group of women with PCOS.(8) However, no randomized controlled trials have been conducted to evaluate the potential benefit of myo-inositol supplementation in preventing pregnancy complications in these women. Methods and analysis This is a prospective, multicenter, double-blind, randomized controlled trial to study the clinical effectiveness and cost-effectiveness of myo-inositol supplementation to prevent pregnancy among women with PCOS. Recruitment will set out to include 464 individuals with PCOS between 8+0 and 16+0 weeks of pregnancy, who are then randomized in a 1:1 ratio to either the intervention group that will receive 4 grams myo-inositol added a standard recommended dose of folic acid, divided over two daily sachets of sugary powder throughout pregnancy; or into the control group that will receive similar looking sachets containing no supplement other than the routinely recommended dose of folic acid. Regular multivitamin use (without inositols) will be allowed for both groups. The primary endpoint is the incidence of the composite outcome of either GDM, preeclampsia and/or preterm birth. Secondary endpoints include indicators of maternal physical and mental well-being, maternal health-related quality of life, neonatal outcomes, breastfeeding practices and breastmilk composition. Trial results will be analysed according to the intention-to-treat principle. A full economic evaluation will be performed. Ethics and dissemination The study protocol has been approved by the Medical Ethics Committee of the Erasmus MC University Medical Centre Rotterdam. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted to peer-reviewed journals. Trial registration number: NTR-NL7799 ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Protocols ### Funding Statement The MYPP-trial is supported by a grant of the Netherlands Organisation for Health Research and Development (ZonMw), grant number 84801 6013. The manufacturer of the supplements (Gideon Richter, Belgium) has no role in the conduct or execution of the trial, apart from manufacturing and delivering the custom-made supplements. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The trial protocol has been approved by the Medical Research Ethics Committee (MREC) of the Erasmus MC University Medical Centre, Rotterdam under the number MEC-2019-000. Approval by the Board of Directors will be obtained for all participating hospitals. The trial is registered in the public Dutch Trial Registry (NTR) under the number NTR-NL7799 in June 2019. MYPP is also registered online at ClinicalTrials.gov under the number [NCT05524259][1] in September 2022. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05524259&atom=%2Fmedrxiv%2Fearly%2F2025%2F04%2F01%2F2025.04.01.25325030.atom

Importance:Pregnant individuals with polycystic ovary syndrome (PCOS) present with a higher risk of pregnancy complications, including gestational diabetes, preeclampsia, and preterm birth. Myo-inositol supplementation may reduce these risks. Objective:To determine whether daily supplementation with myo-inositol during pregnancy among individuals with PCOS reduces the risk of a composite outcome of gestational diabetes, preeclampsia, and preterm birth. Design, Setting, and Participants:This double-blind, placebo-controlled, randomized trial was conducted at 13 hospitals in the Netherlands. Pregnant individuals with PCOS who were between 8 and 16 weeks' gestation were enrolled between June 2019 and March 2023. Final follow-up was complete on December 27, 2023. Analyses were conducted July 2024. Interventions:Participants were randomized on a 1:1 basis to receive sachets with either myo-inositol, 2 g, with 0.2 mg of folic acid twice daily (n = 230) or matching placebo with 0.2 mg of folic acid only (n = 234) until delivery. Main Outcomes and Measures:The primary outcome was a composite of gestational diabetes, preeclampsia, or preterm birth (before 37 weeks' gestation). Results:Among 464 participants, the mean (SD) age was 31.5 (3.8) years; 18 participants (3.9%) reported Asian race and 395 (86.1%) reported White race. The prevalence of biochemical hyperandrogenism was higher at baseline in the myo-inositol group than the placebo group (29.0% [53 of 180] vs 18.5% [37 of 193]). A primary outcome event occurred in 25.0% (n = 56) of participants in the myo-inositol group and 26.8% (n = 61) in the placebo group (relative risk, 0.93 [95% CI, 0.68-1.28]; P = .67). Conclusions and Relevance:Myo-inositol supplementation during pregnancy did not reduce the incidence of a composite of gestational diabetes, preeclampsia, or preterm birth in patients with PCOS. Trial Registration:onderzoekmetmensen.nl Identifier: NL67329.078.18.

Abstract Introduction Gestational diabetes mellitus (GDM), or hyperglycemia first diagnosed in pregnancy, affects 7–10% of all pregnancies worldwide. Perinatal risk rises with increasing glycemia at oral glucose tolerance test (OGTT). The new (2013) WHO criteria recommend a lower fasting, and a higher post-load threshold for GDM diagnosis in comparison to the old (1999) WHO criteria. To date, however, outcomes of GDM treatment for those affected by the altered diagnostic criteria, has not been well investigated. We hypothesized that intensive GDM treatment according to the new (2013) GDM criteria would result in a reduction in infants with birth weight > 90th centile (large for gestational age, LGA), in comparison to treatment according to the old criteria (1999). Methods The TANGO-DM trial is an open label, multicenter randomized controlled trial. Participants are pregnant with a gestational age between 16 + 0 and 32 + 0 weeks, who underwent a 1-step venous 2- or 3-point 75-gram oral OGTT, were eligible if they had glucose concentrations discordant between the old (1999) and the new (2013) criteria. After informed consent, women are randomized to either intensive GDM treatment, consisting of dietary advice and glucose monitoring and, if euglycemia is not reached, antihyperglycemic agents, or normal obstetric care without GDM treatment. The primary outcome is large-for-gestational-age infants (birth weight > 90th percentile). Secondary outcome measures include maternal complications, obstetric complications, neonatal complications, obstetric interventions, quality of life, and healthcare and societal costs. Outcomes will be analyzed according to the intention-to-treat principle. The study is powered to detect a reduction in LGA from 16% in the untreated to 10% in the treated group, which requires 1032 participants (516 per arm; alpha-error 5% for 80% power). Discussion The TANGO-DM trial will provide high-level evidence to support or refute the use of the new 2013 WHO diagnostic criteria in terms of their ability to lower the number of large for gestational age infants and/or improve maternal and perinatal outcomes and/or costs in women with gestational diabetes. Trial registration Central Committee on Research Involving Human Subjects (CCMO) (NL63013.018.18). Registered on 22 September 2018.

BACKGROUND:Pregnancy is a state of increased metabolic demand that necessitates major changes in endocrine physiology. Gestational thyroid dysfunction and gestational diabetes are common endocrine conditions of pregnancy that frequently coincide. Although the effects of thyroid hormones on glucose metabolism are well documented, important knowledge gaps remain in terms of the extent and clinical relevance of these effects during pregnancy. The aim of this meta-analysis is to assess the association of thyroid function test results with gestational diabetes and markers of glucose metabolism. METHODS:In this systematic review and individual participant data meta-analysis, we searched Ovid MEDLINE, EMBASE, and Web of Science from database inception to Dec 12, 2024, for prospective population-based cohort studies with individual patient data on thyroid function, gestational diabetes, and measures of glucose homoeostasis during pregnancy. Furthermore, open invitations to join the Consortium on Thyroid and Pregnancy were issued to identify unpublished datasets. We excluded participants with multiple pregnancies; pre-existing thyroid disease or diabetes; current use of medications that could affect thyroid or glucose levels; or a history of infertility treatment, miscarriage, or stillbirth. Exposures were maternal gestational concentrations of thyroid-stimulating hormone (TSH), free T4 (FT4), free T3 (FT3), and total T3; thyroperoxidase antibody positivity; thyroglobulin antibody positivity; and thyroid disease entities (ie, subclinical hypothyroidism, overt and subclinical hyperthyroidism, and isolated hypothyroxinaemia), which were defined according to current guidelines. The primary outcome was presence of gestational diabetes as defined in individual cohorts. Individual participant data were analysed using generalised linear mixed-effects regression models adjusting for maternal age, BMI, smoking status, parity, ethnicity, fetal sex, and gestational age at blood sampling. We preregistered our study protocol with PROSPERO (CRD42022371927). FINDINGS:We identified 638 published studies with our systematic search, of which 21 studies based on 17 cohorts met inclusion criteria; 11 of these prospective cohort studies provided individual participant data, and data from an additional 14 cohorts were added via personal contacts and open invitations, resulting in a study population of 63 548 participants from 25 cohorts after exclusions. Of the 52 632 participants in 17 cohorts with TPOAb measurements available to define thyroid disease entities, 1687 (3·2%) of these participants had subclinical hypothyroidism, 1153 (2·2%) had isolated hypothyroxinaemia, and 2958 (4·7%) had gestational diabetes. Compared with euthyroidism, isolated hypothyroxinaemia was associated with a higher risk of gestational diabetes (absolute risk 6·5% [72 of 1113] for isolated hypothyroxinaemia vs 3·5% [1555 of 44 787] for euthyroidism; adjusted odds ratio [aOR] 1·52 [95% CI 1·17-1·98], p=0·0017; 45 900 participants). A lower FT4 concentration was associated with a higher risk of gestational diabetes (non-linear, p<0·0001). A higher risk of gestational diabetes was found both with a higher FT3 concentration (aOR 1·18 [95%CI 1·10-1·28], p<0·0001) and with a higher FT3-to-FT4 ratio (non-linear; p<0·0001). No evidence was found of associations of TSH, thyroid antibodies, or other thyroid function test abnormalities with gestational diabetes. I2 statistics for the primary analyses ranged from 0-43%, indicating low to moderate heterogeneity. The funnel plot for overt hyperthyroidism indicated a possibility for publication bias (p=0·049), but funnel plots for all other variables did not. INTERPRETATION:A lower FT4 concentration and isolated hypothyroxinaemia during pregnancy are associated with a higher risk of gestational diabetes. Our results challenge the long-standing notion that subclinical hypothyroidism or thyroid autoimmunity are risk factors for gestational diabetes and support both the risk profile for gestational thyroid dysfunction and ongoing efforts on optimisation of treatment targets for pregnant people taking levothyroxine. Follow-up studies are required to establish to what extent levothyroxine initiation or dose adjustments can affect insulin resistance and antihyperglycaemic therapies during pregnancy. FUNDING:The Netherlands Organization for Scientific Research, ZonMw, and the EU Horizon 2020 Program.

Objective: To characterise pregnant women diagnosed with primary or recurrent cancer who died during pregnancy, during delivery or within 1 year postpartum. Design: A descriptive study. Setting: The registry of the International Network on Cancer, Infertility and Pregnancy (INCIP). Population: Women diagnosed with cancer during pregnancy between 2000 and 2022. Methods: Using the INCIP registry database, we compared the characteristics of all women with cancer who died during pregnancy, delivery or within 1 year postpartum with those of all women with cancer who survived the first year postpartum. Main Outcome Measures: Maternal and tumour characteristics and obstetrical and neonatal outcomes. Results: Of the 2359 women registered in INCIP, there were 131 cases (5.6%) of maternal mortality. Lung cancer (9/14, 64.3% of all registered women with lung cancer), gastro-oesophageal cancer (13/21, 61.9%) and acute leukaemia (17/105, 16.2%) had the highest rates of maternal mortality. Maternal mortality was associated with fewer live births compared with the control group without maternal mortality (99/131, 75.6%, vs 1952/2163, 90.0%; P < 0.001), more elective caesarean sections (64/104, 60.4%, vs 756/1836, 41.2%; P < 0.001) and a lower gestational age at (induced) delivery (34.0 vs 37.1 weeks; P < 0.001), resulting in more preterm births. Conclusions: Maternal mortality occurred in 5.6% of cancer-in-pregnancy cases and is associated with adverse perinatal outcomes.

AimsThe impact of maternal metformin use during pregnancy on fetal, infant, childhood and adolescent growth, development, and health remains unclear. Our objective was to systematically review the available evidence from animal experiments on the effects of intrauterine metformin exposure on offspring's anthropometric, cardiovascular and metabolic outcomes.MethodsA systematic search was conducted in PUBMED and EMBASE from inception (searched on 12th April 2023). We extracted original, controlled animal studies that investigated the effects of maternal metformin use during pregnancy on offspring anthropometric, cardiovascular and metabolic measurements. Subsequently, risk of bias was assessed and meta-analyses using the standardized mean difference and a random effects model were conducted for all outcomes containing data from 3 or more studies. Subgroup analyses were planned for species, strain, sex and type of model in the case of 10 comparisons or more per subgroup.ResultsWe included 37 articles (n = 3133 offspring from n = 716 litters, containing n = 51 comparisons) in this review, mostly (95%) on rodent models and 5% pig models. Follow-up of offspring ranged from birth to 2 years of age. Thirty four of the included articles could be included in the meta-analysis. No significant effects in the overall meta-analysis of metformin on any of the anthropometric, cardiovascular and metabolic offspring outcome measures were identified. Between-studies heterogeneity was high, and risk of bias was unclear in most studies as a consequence of poor reporting of essential methodological details.ConclusionThis systematic review was unable to establish effects of metformin treatment during pregnancy on anthropometric, cardiovascular and metabolic outcomes in non-human offspring. Heterogeneity between studies was high and reporting of methodological details often limited. This highlights a need for additional high-quality research both in humans and model systems to allow firm conclusions to be established. Future research should include focus on the effects of metformin in older offspring age groups, and on outcomes which have gone uninvestigated to date.

Objective To determine efficacy and safety of intrapartum and early postpartum advanced hybrid closed loop (AHCL) therapy compared to standard insulin therapy (SoC) in pregnant individuals with type 1 diabetes (T1D). Research Design and Methods CRISTAL was a double-arm, open-label, randomized controlled trial in Belgium and the Netherlands, in which 95 pregnant participants with T1D were randomly assigned (1:1) to MiniMed™ 780G AHCL (n=46) or SoC (n=49). This prespecified secondary observational analysis focused on differences in glycemic control and safety outcomes between participants from the original AHCL group who continued AHCL intrapartum (n=27) and/or early postpartum (n=37, until hospital discharge) and participants from the original SoC group using SoC intrapartum (n=45) and/or early postpartum (n=34). Results Of the 43 (AHCL) and 46 (SoC) participants completing the trial, 27 (62.8%) continued AHCL and 45 (97.8%) SoC intrapartum, respectively. Compared to SoC, intrapartum AHCL was associated with higher time in range 3.5-7.8 mmol/L (71.5±17.7% vs. 63.1±17.0%, P=0.030), numerically lower time above range >7.8 mmol/L (27.3±17.4% vs. 35.3±17.5%, P=0.054), without increased time below range <3.5 mmol/L (1.1±2.4% vs. 1.5±2.3%, P=0.146). Early postpartum, 37 (86.0%) participants randomized to AHCL used AHCL, with a median increase in insulin-to-carbohydrate ratios of 67% (IQR -14-126). Similar tight glycemic control (3.9-10.0 mmol/L: 86.8±6.7% vs. 83.8±8.1%, P=0.124) was observed with AHCL versus SoC. No severe hypoglycemia or diabetic ketoacidosis was reported in either group. Conclusions AHCL is effective in maintaining tight glycemic control intrapartum and early postpartum and can be safely continued during periods of rapidly changing insulin requirements.