Maternal Pregestational Diabetes Research Articles

Clinical and radiological evaluation of caudal regression syndrome.

Caudal regression syndrome is a form of segmental spinal dysgenesis involving the caudal spinal column, ranging from segmental coccygeal agenesis to extensive thoracolumbar agenesis with varying degrees of spinal cord dysgenesis. A majority of caudal regression cases are sporadic but maternal pre-gestational diabetes mellitus is an important risk factor. Imaging is an integral part of management of caudal regression syndrome. Antenatal diagnosis on obstetric ultrasound and evaluation with fetal MRI is ideal. Early postnatal diagnosis and/or detailed evaluation with MRI is essential for early management to improve outcomes. Pang classification categorizes caudal regression syndrome into two categories based on the position of the conus while Renshaw classification is based on the degree of vertebral column agenesis. Caudal regression syndrome may be associated with several additional anomalies, both spinal and extraspinal. A number of genitourinary and gastrointestinal anomalies have been described in association with caudal regression syndrome. The field of view of MRI of the lumbosacral spine in caudal regression syndrome needs to be extended to visualize the retroperitoneal structures without the use of a saturation band. Syndromic associations may be suspected, and additional imaging performed, based on findings of extended field of view MRI of the spine. Associated sacral masses and filar abnormalities need to be identified and may also require surgical treatment. The multisystem nature of this disease necessitates a multimodality approach to the evaluation and management of caudal regression syndrome with close cooperation between pediatric neuroradiologists and body radiologists as well as multiple clinical teams. Appropriate early management with surgical correction as necessary can significantly improve prognosis and survival in caudal regression syndrome.

Factors Associated with Maternal Morbidity among Black Women in the United States.

Non-Hispanic Black people (NHBP) have a three-fold higher rate of maternal mortality compared to other racial groups. Racial disparities in maternal morbidity are well-described; however, there are substantial differences in cultural, economic, and social determinants of health among racial groups. We thus sought to study the at-risk, non-Hispanic Black population as its own cohort to identify factors most associated with severe maternal morbidity (SMM). This is a population-based retrospective case-control study of all live births in the United States between 2017 and 2019 using birth records obtained from the National Center for Health Statistics. The primary outcome for this study was to determine demographic, social, medical, and obstetric factors associated with maternal morbidity among NHBP who did and did not experience an SMM event. Multivariable logistic regression was used to estimate the adjusted odds ratio between each individual factor and the outcome of SMM among NHBP. Of the 1,624,744 NHBP who delivered between 2017 and 2019, 1.1% experienced an SMM event defined as a composite of blood product transfusion, eclamptic seizure, intensive care unit admission, unplanned hysterectomy, and uterine rupture. The rates of these individual SMM events per 10,000 deliveries were 50, 40, 20, 5, and 4 among NHBP, respectively. Among NHBP, factors associated in multivariable regression analysis with SMM in order of strength of association included cesarean delivery, earlier gestational age at delivery, preeclampsia, induction of labor, chronic hypertension, prior preterm birth, lower educational attainment, multifetal gestation, advanced maternal age, pregestational diabetes, and cigarette smoking. The population attributable fraction for cesarean delivery, preterm birth, and pregnancy-induced hypertensive disease for the outcome of SMM were 0.46, 0.23, and 0.07, respectively. The three factors most associated with SMM among NHBP are potentially avoidable or modifiable by aggressive screening, prevention, and treatment of preeclampsia and preterm birth as well as reducing cesarean rates in this population. · The rate of SMM in NHBP may be modifiable.. · NHBP have a three-fold higher rate of maternal mortality.. · Preeclampsia, preterm birth, and cesarean sections are most associated with maternal morbidity..

Maternal risk factors for congenital vertebral formation and mixed defects: A population-based case–control study

Background: The etiology and risk factors of congenital vertebral anomalies are mainly unclear in isolated cases. Also, there are no reports on the risk factors for different subgroups of vertebral anomalies. Therefore, we assessed and identified potential maternal risk factors for these anomalies and hypothesized that diabetes, other chronic diseases, smoking, obesity, and medication in early pregnancy would increase the risk of congenital vertebral anomalies. Methods: All cases with congenital vertebral anomalies were identified in the Finnish Register of Congenital Malformations from 1997 to 2016 for this nationwide register-based case–control study. Five matched controls without vertebral malformations were randomly selected. Analyzed maternal risk factors included maternal age, body mass index, parity, smoking, history of miscarriages, chronic diseases, and prescription drug purchases in early pregnancy. Results: The register search identified 256 cases with congenital vertebral malformations. After excluding 66 syndromic cases, 190 non-syndromic malformations (74 formation defects, 4 segmentation defects, and 112 mixed anomalies) were included in the study. Maternal smoking was a significant risk factor for formation defects (adjusted odds ratio 2.33, 95% confidence interval 1.21–4.47). Also, pregestational diabetes (adjusted odds ratio 8.53, 95% confidence interval 2.33–31.20) and rheumatoid arthritis (adjusted odds ratio 13.19, 95% confidence interval 1.31–132.95) were associated with mixed vertebral anomalies. Conclusion: Maternal pregestational diabetes and rheumatoid arthritis were associated with an increased risk of mixed vertebral anomalies. Maternal smoking increases the risk of formation defects and represents an avoidable risk factor for congenital scoliosis. Level of evidence: III

Risk of major congenital heart disease in pregestational maternal diabetes is modified by hemoglobin A1c.

The association between pregestational diabetes mellitus (PDM) and risk of congenital heart disease (CHD) is well recognized; however, the importance of glycemic control and other coexisting risk factors during pregnancy is less clear. We sought to determine the relative risk (RR) of major CHD (mCHD) among offspring from pregnancies complicated by PDM and the effect of first-trimester glycemic control on mCHD risk. We determined the incidence of mCHD (requiring surgery within 1 year of birth or resulting in pregnancy termination or fetal demise) among registered births in Alberta, Canada. Linkage of diabetes status, maximum hemoglobin A1c (HbA1c) at < 16 weeks' gestation and other covariates was performed using data from the Alberta Perinatal Health Program registry. Risk of mCHD according to HbA1c was estimated as an adjusted RR (aRR), calculated using log-binomial modeling. Of 1412 cases of mCHD in 594 773 (2.37/1000) births in the study period, mCHD was present in 48/7497 with PDM (6.4/1000; RR, 2.8 (95% CI, 2.1-3.7); P < 0.0001). In the entire cohort, increased maternal age (aRR, 1.03 (95% CI, 1.02-1.04); P < 0.0001) and multiple gestation (aRR, 1.37 (95% CI, 1.1-1.8); P = 0.02) were also associated with mCHD risk, whereas maternal prepregnancy weight > 91 kg was not. The stratified risk for mCHD associated with HbA1c ≤ 6.1%, > 6.1-8.0% and > 8.0% was 4.2/1000, 6.8/1000 and 17.1/1000 PDM/gestational diabetes mellitus births, respectively; the aRR of mCHD associated with PDM and HbA1c > 8.0% was 8.5 (95% CI, 5.0-14.4) compared to those without diabetes and 5.5 (95% CI, 1.6-19.4) compared to PDM with normal HbA1c (≤ 6.1%). PDM is associated with a RR of 2.8 for mCHD, increasing to 8.5 in those with HbA1c > 8%. These data should facilitate refinement of referral indications for high-risk pregnancy screening. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Caudal regression syndrome type 1 with minimally invasive computed tomography and magnetic resonance imaging autopsy: a case report

BackgroundCaudal regression syndrome is a rare complex congenital anomaly with reduced penetrance and phenotypic variability characterized by osseous defects of the caudal spine, lower limb anomalies, and accompanying genitourinary, gastrointestinal/anorectal, and cardiac system soft tissue defects. We report a rare presentation of type 1 caudal regression syndrome in a pregnant woman with preexisting diabetes, in which early recognition of severe fetal anomalies on routine antenatal ultrasound facilitated confirmation with fetal magnetic resonance imaging to characterize extent of disease and prognosticate fetal outcome.Case presentationThis case of type 1 caudal regression syndrome in the setting of maternal pregestational diabetes mellitus resulted in stillbirth. The mother was a 29-year-old Caucasian primigravida female with past medical history of poorly controlled type 2 diabetes managed with metformin prior to pregnancy, prompting admission for glucose management and initiation of insulin at 13 weeks. Baseline hemoglobin A1c was high at 8.0%. Fetal ultrasound at 22 weeks was notable for severe sacral agenesis, bilateral renal pelvis dilatation, single umbilical artery, and pulmonary hypoplasia. Fetal magnetic resonance imaging at 29 weeks showed absent lower two-thirds of the spine with corresponding spinal cord abnormality compatible with type 1 caudal regression syndrome. The mother delivered a male stillborn at 39 and 3/7 weeks. Minimally invasive postmortem magnetic resonance imaging and computed tomography autopsy were performed to confirm clinical findings when family declined conventional autopsy. Etiology of sacral agenesis was attributed to poorly controlled maternal diabetes early in gestation.ConclusionMaternal preexisting diabetes is a known risk factor for development of congenital malformations. This rare case of type 1 caudal regression syndrome in a mother with preexisting diabetes with elevated hemoglobin A1c highlights the importance of preconception glycemic control in diabetic women and the utility of fetal magnetic resonance imaging for confirmation of ultrasound findings to permit accurate prognostication. Additionally, minimally invasive postmortem magnetic resonance imaging and computed tomography autopsy can facilitate diagnostic confirmation of clinical findings in perinatal death due to complex congenital anomalies while limiting the emotional burden on bereaved family members who decline conventional autopsy.

Maternal Pre-Existing Diabetes: A Non-Inherited Risk Factor for Congenital Cardiopathies.

Congenital heart defects (CHDs) are the most common form of birth defects in humans. They occur in 9 out of 1000 live births and are defined as structural abnormalities of the heart. Understanding CHDs is difficult due to the heterogeneity of the disease and its multifactorial etiology. Advances in genomic sequencing have made it possible to identify the genetic factors involved in CHDs. However, genetic origins have only been found in a minority of CHD cases, suggesting the contribution of non-inherited (environmental) risk factors to the etiology of CHDs. Maternal pregestational diabetes is associated with a three- to five-fold increased risk of congenital cardiopathies, but the underlying molecular mechanisms are incompletely understood. According to current hypotheses, hyperglycemia is the main teratogenic agent in diabetic pregnancies. It is thought to induce cell damage, directly through genetic and epigenetic dysregulations and/or indirectly through production of reactive oxygen species (ROS). The purpose of this review is to summarize key findings on the molecular mechanisms altered in cardiac development during exposure to hyperglycemic conditions in utero. It also presents the various in vivo and in vitro techniques used to experimentally model pregestational diabetes. Finally, new approaches are suggested to broaden our understanding of the subject and develop new prevention strategies.

Risk of birth defects in pregnant persons with sleep-disordered breathing during pregnancy.

As many as one in four pregnant women may experience sleep-disordered breathing (SDB) during pregnancy. The same sequelae of SDB, such as insulin resistance and inflammation, have been implicated in the development of certain birth defects. This is a secondary analysis of the SDB substudy of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be study, which included 2106 participants who had a sufficiency sleep study at two visits at different time points in pregnancy. SDB was based on a self-administered home sleep apnea test with data scored by trained, blinded research polysomnologists. SDB was defined as an apnea-hypopnea index (AHI) ≥5. The primary outcome of this analysis was any of the 45 non-chromosomal birth defects included in the National Birth Defects Prevention Network Annual Report. In this cohort, the overall rate of birth defects was 3.1%. The prevalence was similar between those without SDB (3.0%) and those with only mid-pregnancy SDB (3.4%), but was higher in those with early-pregnancy SDB (6.7%). After adjusting for maternal age, chronic hypertension, pregestational diabetes, and body mass index (BMI), there were no statistically significant differences in the risk of birth defects by subject SDB status. Further studies to evaluate the effect of prepregnancy and early-pregnancy SDB on the fetus, as well as the risk of specific birth defects and neonatal outcomes in those with an objectively measured diagnosis of SDB, are still needed.

The Association of Nutrition and Exercise Behaviors of Women with Diabetes in Pregnancy with Infant Breastfeeding Practices.

Background: Although breastfeeding confers significant benefits to infants, women with diabetes in pregnancy experience unique nutrition and health challenges, which may influence infant feeding practice. This study aimed to determine the association between nutrition and exercise behaviors of women with diabetes in pregnancy and breastfeeding at birth and 6 months. Methods: A secondary data analysis of a longitudinal study on maternal pregestational diabetes mellitus (DM) and gestational diabetes (GDM) and infant development was conducted. Women self-reported engaging in nutrition behaviors, such as using meal plans, and exercise health behaviors. Primary outcomes were exclusive breastfeeding at birth and any breastfeeding at 6 months. Logistic regression models adjusted for significant maternal-infant covariates. Results: Of n = 48 women with diabetes in pregnancy, 94% had GDM and 6% had pregestational type 1 or type 2 DM. Forty percent of women exclusively breastfed at birth and 68% partially or exclusively breastfed at 6 months (of n = 34 with complete 6-month data). Women who cooked their own meals had two times greater adjusted odds of exclusive breastfeeding at birth (adjusted odds ratio [AOR] = 1.94, 95% confidence interval [CI] = 1.12-5.11), and women who exercised during pregnancy had seven times greater adjusted odds of any breastfeeding at 6 months (AOR = 7.2, 95% CI = 1.10-42.8). Conclusion: Nutrition and exercise behaviors were associated with exclusive breastfeeding at birth and any breastfeeding at 6 months. Health behaviors to effectively manage diabetes during pregnancy may inform efforts to improve breastfeeding initiation and duration, and future studies in a larger sample are needed.

Abstract P1002: Impact Of Maternal Diabetes-associated Oxidative Stress On The Developing Endocardium

Congenital heart defects (CHD) affect 1% of all live births and are the leading cause of birth defect-related mortality. The etiology of CHD is multifactorial as genomic variation and environmental factors act as contributors. Among the environmental teratogens, maternal pre-gestational diabetes mellitus and its concurrent maternal hyperglycemia (matHG) is associated with a ~5-fold increased risk of CHD. Oxidative stress (Ox-Stress) due to generation of excess reactive oxygen species is observed in embryonic hearts exposed to matHG in animal models, but its teratogenic effect on cardiac development is not understood. Additionally, we observed murine embryonic hearts exposed to matHG have reduced expression of Notch1, which is highly expressed in endocardial cells (EC) and reported a gene-environment interaction between matHG and Notch1 haploinsufficiency that results in CHD in mice. We hypothesize that matHG-induced Ox-Stress leads to the downregulation of endocardial Notch signaling and aberrant EC function leading to CHD. To investigate the effects of matHG-induced Ox-Stress on endocardial Notch signaling, we examined mouse embryos exposed to matHG with conditional deletion of Notch1 in EC. We used lineage tracing to detect differences in EC-derived structures in hyperglycemia and normoglycemia-exposed embryonic hearts. Finally, we asked whether modulating intracellular levels of Ox-Stress can rescue the CHD phenotypes observed with matHG exposure by generating mouse embryos with overexpression of the antioxidant gene, SOD1 . Results show conditional deletion of endocardial Notch1 in embryos exposed to matHG leads to highly penetrant CHD. We found increased Ox-Stress and reduced number of EC-derived mesenchymal cells in endocardial cushions of mouse hearts exposed to matHG. Finally, embryos with SOD1 overexpression have reduced Ox-Stress and decreased incidence of CHD compared to non-SOD1 overexpressing littermates. This works shows that matHG-induced Ox-Stress may be associated with aberrant EC and EC-derived cell function via disruption of Notch signaling. Mitigating Ox-Stress during cardiac development may lead to rescue of Notch signaling and EC function to reduce CHD incidence from matHG exposure.

Association between Sleep Disordered Breathing and Neonatal Outcomes in Nulliparous Individuals.

Our objective was to determine whether objectively measured sleep-disordered breathing (SDB) during pregnancy is associated with an increased risk of adverse neonatal outcomes in a cohort of nulliparous individuals. Secondary analysis of the nuMom2b sleep disordered breathing substudy was performed. Individuals underwent in-home sleep studies for SDB assessment in early (6-15 weeks' gestation) and mid-pregnancy (22-31 weeks' gestation). SDB was defined as an apnea-hypopnea index ≥5 events/h at either time point. The primary outcome was a composite outcome of respiratory distress syndrome, transient tachypnea of the newborn, or receipt of respiratory support, treated hyperbilirubinemia or hypoglycemia, large-for-gestational age, seizures treated with medications or confirmed by electroencephalography, confirmed sepsis, or neonatal death. Individuals were categorized into (1) early pregnancy SDB (6-15 weeks' gestation), (2) new onset mid-pregnancy SDB (22-31 weeks' gestation), and (3) no SDB. Log-binomial regression was used to calculate adjusted risk ratios (RR) and 95% confidence intervals (CIs) representing the association. Among 2,106 participants, 3% (n = 75) had early pregnancy SDB and 5.7% (n = 119) developed new-onset mid-pregnancy SDB. The incidence of the primary outcome was higher in the offspring of individuals with early (29.3%) and new onset mid-pregnancy SDB (30.3%) compared with individuals with no SDB (17.8%). After adjustment for maternal age, chronic hypertension, pregestational diabetes, and body mass index, new onset mid-pregnancy SDB conferred increased risk (RR = 1.43, 95% CI: 1.05, 1.94), where there was no longer statistically significant association between early pregnancy SDB and the primary outcome. New onset, mid-pregnancy SDB is independently associated with neonatal morbidity. · Sleep disordered breathing (SDB) is a common condition impacting pregnancy with known maternal risks.. · Objectively defined SDB in pregnancy was associated with a composite of adverse neonatal outcomes.. · New onset SDB in mid pregnancy conferred statistically significant increased risk..

Maternal Risk Factors for Congenital Vertebral Anomalies: A Population-Based Study.

The spectrum of congenital vertebral defects varies from benign lesions to severe, life-threatening conditions. The etiology and maternal risk factors remain mainly unclear in isolated cases. Hence, we aimed to assess and identify potential maternal risk factors for these anomalies. Based on previous studies, we hypothesized that maternal diabetes, smoking, advanced maternal age, obesity, chronic diseases, and medication used during the first trimester of pregnancy might increase the risk of congenital vertebral malformations. We performed a nationwide register-based case-control study. All cases with vertebral anomalies (including live births, stillbirths, and terminations for fetal anomaly) were identified in the Finnish Register of Congenital Malformations from 1997 to 2016. Five matched controls from the same geographic region were randomly selected for each case. Analyzed maternal risk factors included age, body mass index (BMI), parity, smoking, history of miscarriages, chronic diseases, and prescription drugs dispensed during the first trimester of pregnancy. In total, 256 cases with diagnosed congenital vertebral anomalies were identified. After excluding 66 malformations associated with known syndromes, 190 nonsyndromic malformation cases were included. These were compared with 950 matched controls. Maternal pregestational diabetes was a significant risk factor for congenital vertebral anomalies (adjusted odds ratio [OR], 7.30 [95% confidence interval (CI), 2.53 to 21.09). Also, rheumatoid arthritis (adjusted OR, 22.91 [95% CI, 2.67 to 196.40]), estrogens (adjusted OR, 5.30 [95% CI, 1.57 to 17.8]), and heparins (adjusted OR, 8.94 [95% CI, 1.38 to 57.9]) were associated with elevated risk. In a sensitivity analysis using imputation, maternal smoking was also significantly associated with an elevated risk (adjusted OR, 1.57 [95% CI, 1.05 to 2.34]). Maternal pregestational diabetes and rheumatoid arthritis increased the risk of congenital vertebral anomalies. Also, estrogens and heparins, both of which are frequently used in assisted reproductive technologies, were associated with an increased risk. Sensitivity analysis suggested an increased risk of vertebral anomalies with maternal smoking, warranting further studies. Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Diabetes and Hypertensive Disorders of Pregnancy and the Risk of Third- and Fourth-Degree Perineal Lacerations: A Large United States Cohort 2016–2020 [ID: 1377605

INTRODUCTION: The objective of this study was to assess the effect diabetes and hypertensive disorders of pregnancy have on the rate of third- and fourth-degree perineal laceration (3/4 PL). METHODS: This represents a retrospective cohort based on the Centers for Disease Control and Prevention Natality Live Birth database (2016–2020). We compared the rates of 3/4 PL in term, singleton vaginal births across the United States based on maternal gestational hypertension, preeclampsia, pregestational diabetes, and gestational diabetes. We used Pearson χ2 and multivariate logistic regression to control for confounding variables. Statistical significance was determined as P&lt;.05, and results were displayed as adjusted odds ratios (aORs) with 95% CI. RESULTS: Of the 11,677,671 who met inclusion criteria, 139,174 (1.2%) women experienced 3/4 PL. Gestational hypertension and preeclampsia were associated with increased rates of 3/4 PL (1.53% with aOR 1.28, 95% CI 1.25–1.30, and 1.61% with aOR 1.31, 95% CI 1.06–1.17, respectively). Additionally, both pregestational diabetes and gestational diabetes were associated with higher rates (1.44% with aOR 1.45, 95% CI 1.35–1.56, and 1.44% with aOR 1.27, 95% CI 1.25–1.30, respectively). CONCLUSION: Based on this current U.S. database, we identified several medical complications of pregnancy that are associated with an increased risk for 3/4 PL. Specifically, hypertensive disorders of pregnancy (gestational hypertension and preeclampsia), pregestational as well as gestational diabetes were all associated with significantly increased risks. Understanding these associations may contribute to reduction in the rates of 3/4 PL in gravidas with these conditions.

Impact of intrauterine exposure to maternal diabetes on preterm birth: fetal DNA methylation alteration is an important mediator

BackgroundIn utero exposure to diabetes has been shown to contribute to preterm birth, though the underlying biological mechanisms are yet to be fully elucidated. Fetal epigenetic variations established in utero may be a possible pathway. This study aimed to investigate whether in utero exposure to diabetes was associated with a change in newborn DNA methylation, and whether the identified CpG sites mediate the association between diabetes and preterm birth in a racially diverse birth cohort population.MethodsThis study included 954 mother–newborn pairs. Methylation levels in the cord blood were determined using the Illumina Infinium MethylationEPIC BeadChip 850 K array platform. In utero exposure to diabetes was defined by the presence of maternal pregestational or gestational diabetes. Preterm birth was defined as gestational age at birth less than 37 weeks. Linear regression analysis was employed to identify differentially methylated CpG sites. Differentially methylated regions were identified using the DMRcate Package.Results126 (13%) newborns were born to mothers with diabetes in pregnancy and 173 (18%) newborns were born preterm, while 41 newborns were born both preterm and to mothers with diabetes in pregnancy. Genomic-wide CpG analysis found that eighteen CpG sites in cord blood were differentially methylated by maternal diabetes status at an FDR threshold of 5%. These significant CpG sites were mapped to 12 known genes, one of which was annotated to gene Major Histocompatibility Complex, Class II, DM Beta (HLA-DMB). Consistently, one of the two identified significant methylated regions overlapped with HLA-DMB. The identified differentially methylated CpG sites mediated the association between diabetes in pregnancy and preterm birth by 61%.ConclusionsIn this US birth cohort, we found that maternal diabetes was associated with altered fetal DNA methylation patterns, which substantially explained the link between diabetes and preterm birth.

Association of increased fetal epicardial fat thickness with maternal pregestational and gestational diabetes

Objective To evaluate the changes of fetal epicardial fat thickness (EFT) in pregnancies with pregestational diabetes mellitus (PGDM) and gestational diabetes mellitus (GDM) and to identify the diagnostic effectiveness of fetal EFT in differentiating PGDM and GDM from normal pregnancies. Methods The study was conducted with pregnant women who admitted to perinatology department between October 2020 and August 2021. Patients were grouped as PGDM (n = 110), GDM (n = 110), and control (n = 110) for comparison of fetal EFT. EFT was measured in all three groups at 29 weeks of gestation. Demographic characteristics and ultrasonographic findings were recorded and compared. Results The mean fetal EFT was significantly higher in PGDM (1.47 ± 0.083 mm, p < .001) and GDM (1.40 ± 0.082 mm, p < .001) groups compared to control group (1.19 ± 0.049 mm) and was also significantly higher in PGDM group than GDM group (p < .001). Fetal EFT was significantly positively correlated with maternal age, fasting, 1st hour, 2nd hour glucose values, HbA1c, fetal abdominal circumference, and deepest vertical pocket of amniotic fluid (p < .001). Fetal EFT value of 1.3 mm diagnosed PGDM patients with a sensitivity of 97.3% and a specificity of 98.2%. Fetal EFT value of 1.27 mm diagnosed GDM patients with a sensitivity of 94% and a specificity of 95%. Conclusions Fetal EFT is greater in pregnancies with diabetes than in normal pregnancies, and also greater in PGDM than in GDM. In addition, fetal EFT is strongly correlated with maternal blood glucose levels in diabetic pregnancies.

Transcriptional associations between maternal pregestational diabetes, congenital heart defects, and the human placenta

A critical role has been recognized for the placenta in the development of congenital heart defects (CHD), for which infants of pregestationally diabetic (PGDM) mothers are at pronounced risk. PGDM induces stark histological and gross anatomical changes in the placenta, yet little is known about the PGDM placenta’s role in CHD. High-throughput transcriptomic processes have enabled large-scale association between the gene expression signatures of the heart, placenta, and diabetic state. However, limited integrative data exists, necessitating a comparative appraisal of existing literature to identify placental and cardiac signaling pathways that may be altered in the PGDM state.

Association between masked hypertension and late-onset fetal growth restriction at advanced maternal age

Fetal growth restriction (FGR) is a major risk factor for complicated pregnancy including stillbirth. The all-pathophysiology results in uteroplacental insufficiency. Hypertension chronic or pregnancy-related complicates the all-prenatal periods. The relationship between fetal growth restriction and hypertension is well-known and this risk increases with maternal age. Late-onset FGR is diagnosed &gt;32 weeks. Masked hypertension (MH) is a phenotype of hypertension when clinic blood pressure is in the normal range in the office but elevated outside the office. This study examined the risk of late-onset FGR and masked hypertension at advanced maternal age. Sixty pregnant women over 40 years old were included in the study who delivered at our hospital with late-onset fetal growth restriction diagnosis. After taking detailed anamnesis from all individuals included in the study, detailed physical examination, obstetric examination and ambulatory blood pressure monitoring (ABPM) were performed. Women with maternal chronic hypertension, pregestational or gestational diabetes mellitus, chronic kidney disease, rheumatoid disease history, tobacco use, cardiac arrhythmia, fetal genetic abnormality or placental abnormality were excluded from the study. The prevalence of masked hypertension was statistically significantly higher in the group with late intrauterine growth. (n:13, 43% vs n:5, 16.7% p=0.02). Office systolic BP (125.5±4.1 mmHg vs 118.5±5.7 mmHg p=0.016), 24-hour systolic BP measurement (125±9 mmHg vs 119.7±5.7 mmHg p=0.03), and ambulatory nocturnal diastolic BP measurement (66.7±10 mmHg vs. 61.±5.5 mmHg p=0.03) was higher in the group with late FGR. Hypertension can lead to complications in the perinatal period. There is a bad association between FGR and hypertension. Masked hypertension should be considered especially in advanced age pregnant individuals with FGR.

In utero Exposure to Maternal Diabetes and the Risk of Cerebral Palsy: A Population-based Cohort Study.

Evidence on the effects of in utero exposure to maternal diabetes on cerebral palsy (CP) in offspring is limited. We aimed to examine the effects of pregestational (PGDM) and gestational diabetes (GDM) separately on CP risk and the mediating role of increased fetal size. In a population-based study, we included all live births in Ontario, Canada, between 2002 and 2017 followed up through 2018 (n = 2,110,177). Using administrative health data, we estimated crude and adjusted associations between PGDM or GDM and CP using Cox proportional hazards models to account for unequal follow-up in children. For the mediation analysis, we used marginal structural models to estimate the controlled direct effect of PGDM (and GDM) on the risk of CP not mediated by large-for-gestational age (LGA). During the study period, 5,317 children were diagnosed with CP (187 exposed to PGDM and 171 exposed to GDM). Children of mothers with PGDM showed an increased risk (hazard ratio [HR]: 1.84 [95% confidence interval (CI): 1.59, 2.14]) after adjusting for maternal sociodemographic and clinical factors. We found no associations between GDM and CP (adjusted HR: 0.91 [0.77, 1.06]). Our mediation analysis estimated that LGA explained 14% of the PDGM-CP association. In this population-based birth cohort study, maternal pregestational diabetes was associated with increased risk of CP, and the increased risk was not substantially mediated by the increased fetal size.

Changes in fetal intracranial anatomy during maternal pregestational and gestational diabetes.

To evaluate the changes in fetal intracranial structures in pregnant women with pregestational diabetes mellitus (DM) and gestational diabetes mellitus (GDM). The study was conducted prospectively with patients who were grouped as pregestational DM (n=110), GDM (n=110), and control (n=110). Fetal ultrasonographic measurements of widths of posterior lateral ventricles (PLV), cavum septum pellucidi (CSP), cisterna magna (CM), thalamus and transcerebellar diameter (TCD) were recorded and compared. Fetal PLV, CSP, and CM widths were higher in pregestational DM and GDM groups than in control group, and also higher in pregestational DM group compared to GDM group (p < 0.001). Fetal TCD in the PGDM group was found to be less than both control and GDM groups (p < 0.001). No difference was found between three groups in terms of fetal thalamus size (p=0.801). Fetal PLV, CSP, and CM values were positively correlated with maternal hyperglycemia, fetal abdominal circumference (AC), and deepest vertical pocket of amniotic fluid (DVP) (p < 0.001). Fetal TCD was negatively correlated with HbA1c and DVP (p=0.002, p=0.38, respectively). The optimal cut-off points to identify pregestational DM and GDM were 5.55 and 5.83 mm for PLV, 5.83 and 6.32 mm for CSP, and 7.26 and 6.62 mm for CM. Maternal hyperglycemia was significantly associated with an increase in the widths of fetal PLV, CSP, and CM and a decrease in fetal TCD.

Association of prenatal modifiable risk factors with attention-deficit hyperactivity disorder outcomes at age 10 and 15 in an extremely low gestational age cohort.

The increased risk of developing attention-deficit hyperactivity disorder (ADHD) in extremely preterm infants is well-documented. Better understanding of perinatal risk factors, particularly those that are modifiable, can inform prevention efforts. We examined data from the Extremely Low Gestational Age Newborns (ELGAN) Study. Participants were screened for ADHD at age 10 with the Child Symptom Inventory-4 (N = 734) and assessed at age 15 with a structured diagnostic interview (MINI-KID) to evaluate for the diagnosis of ADHD (N = 575). We studied associations of pre-pregnancy maternal body mass index (BMI), pregestational and/or gestational diabetes, maternal smoking during pregnancy (MSDP), and hypertensive disorders of pregnancy (HDP) with 10-year and 15-year ADHD outcomes. Relative risks were calculated using Poisson regression models with robust error variance, adjusted for maternal age, maternal educational status, use of food stamps, public insurance status, marital status at birth, and family history of ADHD. We defined ADHD as a positive screen on the CSI-4 at age 10 and/or meeting DSM-5 criteria at age 15 on the MINI-KID. We evaluated the robustness of the associations to broadening or restricting the definition of ADHD. We limited the analysis to individuals with IQ ≥ 70 to decrease confounding by cognitive functioning. We evaluated interactions between maternal BMI and diabetes status. We assessed for mediation of risk increase by alterations in inflammatory or neurotrophic protein levels in the first week of life. Elevated maternal BMI and maternal diabetes were each associated with a 55-65% increase in risk of ADHD, with evidence of both additive and multiplicative interactions between the two exposures. MSDP and HDP were not associated with the risk of ADHD outcomes. There was some evidence for association of ADHD outcomes with high levels of inflammatory proteins or moderate levels of neurotrophic proteins, but there was no evidence that these mediated the risk associated with maternal BMI or diabetes. Contrary to previous population-based studies, MSDP and HDP did not predict ADHD outcomes in this extremely preterm cohort, but elevated maternal pre-pregnancy BMI, maternal diabetes, and perinatal inflammatory markers were associated with increased risk of ADHD at age 10 and/or 15, with positive interaction between pre-pregnancy BMI and maternal diabetes.

Single-cell transcriptomic profiling unveils dysregulation of cardiac progenitor cells and cardiomyocytes in a mouse model of maternal hyperglycemia

Congenital heart disease (CHD) is the most prevalent birth defect, often linked to genetic variations, environmental exposures, or combination of both. Epidemiological studies reveal that maternal pregestational diabetes is associated with ~5-fold higher risk of CHD in the offspring; however, the causal mechanisms affecting cardiac gene-regulatory-network (GRN) during early embryonic development remain poorly understood. In this study, we utilize an established murine model of pregestational diabetes to uncover the transcriptional responses in key cell-types of the developing heart exposed to maternal hyperglycemia (matHG). Here we show that matHG elicits diverse cellular responses in E9.5 and E11.5 embryonic hearts compared to non-diabetic hearts by single-cell RNA-sequencing. Through differential-gene-expression and cellular trajectory analyses, we identify perturbations in genes, predominantly affecting Isl1+ second heart field progenitors and Tnnt2+ cardiomyocytes with matHG. Using cell-fate mapping analysis in Isl1-lineage descendants, we demonstrate that matHG impairs cardiomyocyte differentiation and alters the expression of lineage-specifying cardiac genes. Finally, our work reveals matHG-mediated transcriptional changes in second heart field lineage that elevate CHD risk by perturbing Isl1-GRN during cardiomyocyte differentiation. Gene-environment interaction studies targeting the Isl1-GRN in cardiac progenitor cells will have a broader impact on understanding the mechanisms of matHG-induced risk of CHD associated with diabetic pregnancies.