Maternal Midpregnancy Glucose Levels and Risk of Congenital Heart Disease in Offspring

Abstract

IMPORTANCE There is a well-described association between maternal diabetes mellitus and risk of congenital heart disease (CHD) in offspring. Although the clinical diagnoses of type 2 diabetes or gestational diabetes are strong risk factors for CHD, subclinical abnormalities of glucose and insulin metabolism are common within the general population and could also confer risk for CHD. We hypothesize that continuous measures of blood analytes related to maternal diabetes are related to odds of cardiac malformations. OBJECTIVE To explore the potential association of 2 different CHD phenotypes in offspring with maternal midpregnancy measures of glucose and insulin. DESIGN, SETTING, AND PARTICIPANTS Case-control study from a population-based cohort of 277 pregnant women in southern and central California carrying infants with tetralogy of Fallot (TOF) (n = 55), dextrotransposition of the great arteries (dTGA) (n = 42), or healthy infants without CHD (n = 180). Serum samples were collected from 2003 through 2007. The analysis was conducted from March through June 2015.MAIN OUTCOMES AND MEASURES Blood analytes related to maternal glucose metabolism were measured from random nonfasting second-trimester blood samples. We measured serum insulin levels by a validated radioimmunoassay, and we measured glucose levels. Multivariable logistic regression models estimated the association between these levels and case status.

Epigenetic mechanisms underlying maternal diabetes-associated risk of congenital heart disease

“…It was recently reported that diabetes-induced elevation of maternal blood glucose levels during the 15th-18th week of gestation were correlated with CHD in a California-based case-control study (73). A mild but statistically significant increase in maternal serum glucose was associated with tetralogy of Fallot, a conotruncal heart defect, in offspring relative to unaffected controls, implying that subtle alterations in maternal glucose have the potential to serve as an environmental risk factor for CHD (73).…”

“…It was recently reported that diabetes-induced elevation of maternal blood glucose levels during the 15th-18th week of gestation were correlated with CHD in a California-based case-control study (73). A mild but statistically significant increase in maternal serum glucose was associated with tetralogy of Fallot, a conotruncal heart defect, in offspring relative to unaffected controls, implying that subtle alterations in maternal glucose have the potential to serve as an environmental risk factor for CHD (73). These findings, in combination with our work, suggest a gene-environment interaction model where increasing maternal glucose levels interact to reduce Notch1 expression levels to cause CHD, and this interaction is sensitized by genetic susceptibility loci, i.e., Notch1 haploinsufficiency, to cross a threshold for CHD occurrence ( Figure 7B).…”

Perinatal mortality in Japanese women diagnosed with gestational diabetes mellitus and diabetes mellitus

“…Blood glucose levels in pregnant women in their first and second trimesters are associated with a risk of fetal malformation. [1][2][3] For example, fetal malformation rates were 0.8% (1/128) and 7.5% (22/292) in women with insulin-dependent diabetes with metabolic control before conception and after gestational week (GW) 8, respectively, compared to 1.4% in control women without diabetes. 1 Random second trimester blood glucose level is elevated in mothers of offspring with tetralogy of Fallot relative to controls (median 97 vs 91.5 mg/dL).…”

Transgenerational cardiology: One way to a baby's heart is through the mother

“…Mouse chow contains a high concentration of folic acid, and there was no difference between young and old mothers in serum homocysteine or B12 levels or red blood cell indices (unpublished data). Maternal hyperglycemia (Priest et al, 2015), pre-pregnancy diabetes (Oyen et al, 2016) and obesity (Cedergren and Kallen, 2003; Gilboa et al, 2010; Madsen et al, 2013) are difficult to disentangle from aging in epidemiologic studies, but easily induced by a high-fat diet in the mouse. The diet had no effect on the incidence of heart defects among the offspring of young mothers, who were markedly hyperglycemic and glucose intolerant.…”

“…Glucose and phenylalanine are prototypical examples in which supraphysiologic maternal levels can cause cardiac malformation (Hachisuga et al, 2015; Levy et al, 2001). Interestingly, the mothers of babies who have tetralogy of Fallot have a mildly elevated level of glucose at midgestation (Priest et al, 2015). A subclinical, quantitative alteration in the concentration of a maternal molecule may not cause a heart defect but could increase risk in offspring who have a genetic predisposition.…”