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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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.

Impact of rural residence and low socioeconomic status on rate and timing of prenatal detection of major congenital heart disease in a jurisdiction of universal health coverage.

OBJECTIVE: Socioeconomic status (SES) and distance of residence from tertiary care may impact fetal detection of congenital heart disease (CHD), partly through reduced access to and quality of obstetric ultrasound screening. It is unknown whether SES and remoteness of residence (RoR) affect prenatal detection of CHD in jurisdictions with universal health coverage. We examined the impact of SES and RoR on the rate and timing of prenatal diagnosis of major CHD within the province of Alberta in Canada. METHODS: In this retrospective study, we identified all fetuses and infants diagnosed with major CHD in Alberta, from 2008 to 2018, that underwent cardiac surgical intervention within the first year after birth, died preoperatively, were stillborn or underwent termination. Using maternal residence postal code and geocoding, Chan SES index quintile, geographic distance from a tertiary-care fetal cardiology center and the Canadian Index of Remoteness (IoR) were calculated. Outcome measures included rates of prenatal diagnosis and diagnosis after 22 weeks' gestation. Risk ratios (RR) were calculated using log-binomial regression and stratified by rural (≥ 100 km from tertiary care) or metropolitan (< 100 km from tertiary care) residence, adjusting for year of birth and the obstetric ultrasound screening view in which CHD would most likely be detected (four-chamber view; outflow-tract view; three-vessel or three-vessels-and-trachea or non-standard view; septal view). RESULTS: Of 1405 fetuses/infants with major CHD, prenatal diagnosis occurred in 814 (57.9%). Residence ≥ 100 km from tertiary care (adjusted RR, 1.19; 95% CI, 1.05-1.34) and higher IoR (adjusted RR, 1.9; 95% CI, 1.1-3.3) were associated with missed prenatal diagnosis of major CHD. Similarly, residence ≥ 100 km from tertiary care (adjusted RR, 1.41; 95% CI, 1.22-1.62) and higher IoR (adjusted RR, 3.6; 95% CI, 2.2-8.2) were associated with prenatal diagnosis after 22 weeks. Although adjusted and unadjusted analyses showed no association between Chan SES index quintile and prenatal-diagnosis rate overall nor for residence in rural areas, in metropolitan regions, lower SES quintiles were associated with missed prenatal diagnosis (quintile 1: RR, 1.24; 95% CI, 1.02-1.50) and higher risk of diagnosis after 22 weeks' gestation (quintile 1: RR, 1.46; 95% CI, 1.10-1.93; quintile 2: RR, 1.66; 95% CI, 1.24-2.23). CONCLUSIONS: Despite universal healthcare, rural residence in Alberta is associated with lower rate of prenatal diagnosis of major CHD and higher risk of late prenatal diagnosis (≥ 22 weeks). Within metropolitan regions, lower SES impacts negatively prenatal-diagnosis rate and timing. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Prenatal features of ductus arteriosus-related branch pulmonary stenosis in fetal pulmonary atresia.

OBJECTIVE: Ductus arteriosus (DA)-related branch pulmonary stenosis (PS), due to ductal tissue migration into the proximal pulmonary artery (PA) ipsilateral to the DA, is common in newborns with pulmonary atresia (PAtr) and contributes significantly to their mortality and morbidity. We sought to define fetal echocardiographic predictors of DA-PS in PAtr. METHODS: This was a study of all neonates diagnosed prenatally with PAtr and a DA-dependent pulmonary circulation, with a DA that joined the underbelly of the arch, who had undergone surgical or catheter intervention in our hospital between 2009 and 2018. The postnatal echocardiograms and clinical records were reviewed to confirm the presence or absence of DA-PS based on the need for angioplasty at initial intervention and/or development of proximal PA stenosis post intervention. Fetal echocardiograms were examined for the features of DA-PS. RESULTS: Of 53 fetuses with PAtr, 34 (64%) had analyzable images, including 20/34 (59%) with and 14/34 (41%) without DA-PS. An inability to visualize the branch PAs in the same plane, largely associated with abnormal DA insertion into the ipsilateral PA (85% of cases), had sensitivity, specificity and positive (PPV) and negative (NPV) predictive values of 75%, 100%, 100% and 74%, respectively, for the prediction of postnatal DA-PS. The mean branch PA posterior bifurcation angle was more obtuse in cases with DA-PS compared to cases without DA-PS (117° ± 17° vs 79° ± 17°, P < 0.001), and an angle of > 100°, the preoperative cut-off observed previously in affected newborns, had a sensitivity, specificity, PPV and NPV of 88%, 79%, 82% and 85%, respectively. The receiver-operating-characteristics curve revealed an angle of ≥ 105° to have a sensitivity and specificity of 88% and 93%, respectively, for prenatal prediction of DA-PS. The presence of one or both features (inability to image in the same plane and the posterior bifurcation angle of ≥ 105°) had a sensitivity, specificity, PPV and NPV of 100%, 93%, 95% and 100%, respectively. CONCLUSION: An inability to visualize the branch PAs in the same plane, associated with abnormal insertion of the DA in most cases, and/or the presence of a posterior PA bifurcation angle of ≥ 105° are predictive features of postnatal DA-PS in fetuses with PAtr. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Fetal echocardiographic predictors of biventricular circulation in hypoplastic left heart complex.

OBJECTIVES: To determine which echocardiographic features of hypoplastic left heart complex (HLHC) in the fetal period are predictive of biventricular (BV) circulation and to evaluate the long-term outcome of patients with HLHC, including rates of mortality, reintervention and development of further cardiac disease. METHODS: Echocardiograms of fetuses with HLHC obtained at 18-26 weeks and 27-36 weeks' gestation between 2004 and 2017 were included in the analysis. The primary outcome was successful BV circulation (Group 1). Group 2 included patients with single-ventricle palliation, death or transplant. Univariate analysis was performed on data obtained at 18-26 and 27-36 weeks and multivariate logistic regression was performed on data obtained at 27-36 weeks only. RESULTS: Of the 51 included cases, 44 achieved successful BV circulation (Group 1) and seven did not (Group 2). Right-to-left/bidirectional foramen ovale (FO) flow and a higher mitral valve (MV) annulus Z-score were associated with successful BV circulation on both univariate and multivariate analysis. Bidirectional or left-to-right FO flow, left ventricular length (LVL) Z-score of < -2.4 and a MV Z-score of < -4.5 correctly predicted 80% of Group 2 cases. Late follow-up was available for 41 patients. There were two late deaths in Group 2. Thirteen patients in Group 1 required reintervention, 12 developed mitral stenosis and five developed isolated subaortic stenosis. CONCLUSIONS: BV circulation is common in fetuses with HLHC. Higher MV annulus and LVL Z-scores and right to left direction of FO flow are important predictors of BV circulation. Long-term sequelae in those with BV circulation may include mitral and subaortic stenosis. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Effects of experimental diabetes on axonal and Schwann cell changes in sciatic nerve isografts.

A reduced ability to regenerate peripheral axons may be partly responsible for diabetic neuropathy. The source of the impairment has not been narrowed down to axonal or Schwann cell failure. We used nerve grafts from control or diabetic donor rats transplanted into control or diabetic hosts to pursue this differential diagnosis. An isograft between the left sciatic nerves of inbred Lewis rats was performed 8 weeks after STZ treatment and on age-matched controls. The nerve exchanges were control-control, control-diabetic, diabetic-control and diabetic-diabetic. At postsurgical day 14, nerves were excised and analysed for levels of axonal markers, total and phosphorylated neurofilament, and Schwann cell receptors, ErbB2 and p75(NTR), using immunohistochemistry and Western blotting. The aim was to measure ingress of axonal markers into the graft and judge the appropriateness of Schwann cell phenotype changes. Transfer of nerve from diabetic to control rats resulted in a doubling in neurofilament, both phosphorylated and nonphosphorylated (both P<0.05). ErbB2 was decreased in grafts from diabetic rats (53% of control, P<0.05) and p75(NTR) levels were increased in both types of graft in diabetic rats (to 300-400% of controls, P<0.05). Schwann cells in diabetic nerve grafts showed receptor levels more similar to controls when placed into a normal environment and the converse also appeared to hold. TUNEL staining revealed increased apoptosis in diabetic nerve distal to the graft. The data show that alterations in Schwann cell phenotype in diabetes are reversed by transfer to control rats and develop in normal nerve after transfer to a diabetic host.

Standardisation of a self-report questionnaire for use in evaluating cognitive, affective and behavioural side-effects of anti-epileptic drug treatments.

The development and standardisation of an inventory for measuring anti-epileptic drug effects on cognition and affect is described. The Side Effect and Life Satisfaction inventory (SEALS) was derived from symptoms and side-effects reported by a patient population. It was administered to 45 patients on two occasions and test-retest reliability was demonstrated. It was administered to 923 patients with epilepsy. An underlying factor structure was produced by principal components analysis, consisting of five sub-scales which were stable when data from males and females were analysed separately or together. Validity was evaluated by comparing inventory scores of patients undergoing a number of treatment trials to show that the inventory was sensitive to treatment differences when other variables were controlled. Patients taking two or more anti-epileptic drugs had poorer SEALS scores than those taking a single drug. Patients taking vigabatrin and one other AED had poorer scores than those taking lamotrigine (LTG) and one other AED. A comparison of changes from baseline to week 4 of a double blind comparison of carbamazepine (CBZ) and LTG showed significantly greater improvement in SEALS scores for patients taking LTG, and significantly poorer scores in those patients taking CBZ who dropped out of the study, than in those who continued. It is concluded that SEALS is a valid and reliable tool for use in anti-epileptic drug trials.