Preconception Glycemic Control: Reducing Risk of Congenital Heart Defect in Offspring

1. Introduction

Congenital heart defects (CHD), or the structural malformations of the heart or great vessels, are the most common birth defects worldwide. Though the exact etiology of CHD remains uncertain, with the cause of most CHD cases remaining unknown and about 20% being attributed to chromosomal or genetic disorders, many cases are supported by evidence of multifactorial causes, with maternal diabetes having well-backed research and consistent association with heightened CHD risk [1,2]. The association between maternal diabetes mellitus and fetal CHD has much to do with timing. The bulk of cardiogenesis, including specification and migration of cardiac neural crest cells (CNCCs) and heart septation to divide the four major atrioventricular chambers, occurs within the first seven weeks of gestation [3,4]. In many pregnancies, this window of cardiac formation takes place before clinical confirmation, let alone care, of the pregnancy [5]. Thus, there remains a question of clinical implications: what does the development of the heart tell us about when and how environmental factors like hyperglycemia can produce teratogenic effects, and what care and hyperglycemia management strategies can be effective for reducing risk of CHD, and when will implementation enable effectiveness?

The association between maternal hyperglycemia and CHD is substantially supported epidemiologically [6], but the literature that addresses the question above has not been synthesized to one cohesive review, and this leaves many separated factors to address: embryology of fetal heart development, biological mechanisms of diabetic embryopathy, studies of glycemic risk to CHD, and evaluation of preconception care (PCC) effectiveness. Although these fragments have been researched and developed to great lengths, there is limited quantity of reviews connecting evidence to practice.

Thus, this review synthesizes evidence across molecular and cellular mechanisms of maternal hyperglycemia disruption of heart development, thresholds for clinical risk, and evidence for the effectiveness of PCC as preventive measures to CHD, as well as challenges to implementation of these measures and future directions of study. Moreover, this narrative review aims for clarification of the necessity of implementing glycemic control measures, particularly before conception, for the prevention of CHD, as well as to identify areas requiring a greater evidence base.

2. Epidemiological Problem

CHD is an abnormal structural defect of the heart and/or great vessels that is present at birth and interferes with the normal flow of blood [7]. CHD is a leading cause of infant and child mortality, with 1.35 million new CHD births every year and an annual count of 250,000 deaths caused by CHD. Among all CHD deaths in 2017, 180,624 occurred in infants less than one year old [8]. In 2016, adjusted for maternal, parental, and infant demographic influences, the odds ratio (OR) for CHD in offspring whose mothers had Type 1 diabetes mellitus (T1DM) is 2.32, with 95% Confidence Interval 1.66-3.25, while the OR for CHD in offspring whose mothers had Type 2 diabetes mellitus (T2DM) is 2.85, with 95% CI 2.60-3.12 [6]. Consistent with the adjusted ORs, it was reported in 2016 that CHD is approximately 2-5 times more likely to affect pregnancies of women with pregestational diabetes mellitus, or diabetes existing before pregnancy, compared to women without diabetes [9].

This review focuses on the impact of pregestational diabetes, rather than gestational diabetes, on fetal cardiac development, risk of CHD, and implications for screening practices and prevention measures. Gestational diabetes is hyperglycemia that is first detected during pregnancy and is also associated with greater instances of CHD in infants, though to a lesser extent than pregestational diabetes (adjusted relative risk (RR) for cyanotic CHD in 2020 was 1.50 for gestational diabetes, versus 4.61 for pregestational diabetes). This observation is supported when considering that screening for gestational diabetes mellitus occurs when the mother is between 24 and 28 weeks pregnant, after the fetus has undergone the critical periods of development [10]. As about 130 million women between the ages of 20 and 49 years old worldwide are diagnosed with diabetes mellitus and maternal diabetes impacted about 21 million births [11], understanding the risk stratification for CHD and the role of treating hyperglycemia in preventing infant and pediatric CHD remains a critical topic to discuss.

3. Mechanism: Hyperglycemia as a Cardiac Teratogen

3.1. Embryonic Cardiac Development

Cardiac development begins early in gestation, as the heart is needed by the end of gestational week 3 for oxygen and nutrient distribution, once passive oxygen diffusion is no longer enough for the developing embryo’s metabolic functions [3]. Development initiates during the presomitic stage of the embryo, or days 8-18 of development, as the organization of cardiac areas and crescent occurs during gastrulation, around the end of the second week of development [4], and develops to form two endocardial tubes covered with myocardial lineage cells [12]. This initial heart tube is formed from first heart field cells [4], after which, during the morphogenic stage (weeks 4-8 of embryonic development) [12], second heart field cardiac progenitor cells proliferate and differentiate into new cardiomyocytes that are added to the straight heart tube while it is looping, growing the heart tube to five times its initial length [4]. As the tube loops rightward, a ventricular formation begins to form where the tube curves outward, and trabecular growth, regulated by NOTCH1 and facilitated by cardiac jelly acting as an extracellular matric, leads to compaction of trabeculae, or the thickening and lengthening of the ventricular myocardium, which occurs after cardiac jelly disappears and allows for cell-to-cell contact [3,4] . Cardiac jelly in the atrioventricular area gives rise to four major endocardial cushions [4]. Septation occurs between the 26^th and 37^th days of gestation, as these cushions develop to begin dividing the heart into what becomes its final four chambers [4,12]. Fusion of two major atrioventricular cushions with the mesenchymal cap of the primary atrial septum and the dorsal mesocardial protrusion (DMP; regulated by Sonic Hedgehog) allows for closure of the ostium primum [4]. Concurrently, the muscular interventricular septum forms from a muscular projection that grows from the ventricular floor, and a membranous septum, composed of endocardial cushion and outflow tract ridges [4], joins the myocardial septum, completing the full septation of the atrioventricular heart by the 7^th week of gestation [12].

3.2. Cardiac Neural Crest Cells: Role in Cardiac Development and Impact of Gylcemic Disruption

CNCCs are a subset of the neural crest cells (NCC), a broader category of multipotent cells that composes the peripheral nervous system and craniofacial areas, that migrate from the dorsal neural tube to the heart, where they contribute to outflow tract septation and the membranous interventricular septum [12,13,14]. As cardiovascular development depends on various signaling pathways for normal specification, migration, and differentiation of CNCCs, a loss or dysregulation of any steps along the relatively long process leads to a variety of CHDs. While the embryo undergoes gastrulation, BMP, WNT, NOTCH, Hippo, and other such pathways are crucial for neural crest progenitors to gain migratory potential through epithelial-to-mesenchymal transition. The CNCCs migrate to pharyngeal arches three, four, and six to form the great arteries, such as the aortic arch, common carotid, and ductus arteriosus. Some remain to continue development of patterning of smooth muscle, while other CNCCs continue migration to the outflow tract and facilitate aorticopulmonary septation [14].

Loss of functional Pax3, a member of the Pax gene family responsible for encoding transcription factors that bind to DNA and are crucial in metazoan development, results in cardiac outflow tract defects, one of the most common human diabetic pregnancy malformations, with 100% penetrance in mouse models. Maternal hyperglycemia, through oxidative stress, inhibits CNCC migration, which would otherwise allow for Pax3 expression. This then prevents Pax3, as an upstream regulator of p53-dependent apoptosis, from suppressing cell death. Subsequently, the CNCC population depletes, increasing cardiac outflow tract defects. However, treatment with vitamin E and GSH-EE could allow for normal CNCC migration and mitigate CHD [1].

Glucose is considered a major teratogen, as improving glycemic control is associated with decreased risk of pregnancy loss and congenital malformation [15], and maternal diabetes is especially teratogenic to the cardiovascular and central nervous system. CNCCs are especially vulnerable to this threat, as gene expression alteration could occur at CNCC migration, among various other stages of heart development, due to hyperglycemia [16]. While maternal diabetes allows for a plethora of threats to the embryo, in an in vivo study using mouse models, it was found that after removing these other factors and localizing to just the uterus and its blood supply, hyperglycemia still demonstrated marked increase in embryopathy prevalence and severity [15].

3.3. Hyperglycemia in Epigenetic Modulation

The pathway involving CNCC is one of several mechanisms by which hyperglycemia may lead to CHD in offspring. Hyperglycemia may result in CHD through DNA epigenetic modification, as seen in murine and Drosophila models, both in vitro and in vivo. Hyperglycemia causes reactive oxygen species (ROS) to accumulate in the embryo’s blood vessels, which then alters the open chromatin upstream of the Nos3 locus, reducing its accessibility and decreasing the availability of nitric oxide (NO). Subsequently, expression of the transcriptional repressor Jarid2 is increased, which further reduces Notch1 levels below the critical threshold required for normal development of the fetal heart [17].

Besides the sequence impacting Notch1, DNA methylation is associated with rise of CHD in the offspring in a broader sense, as conditional knock-out of DNA methyl transferase 3-B is associated with ventricular septal defects and endocardial cushion defects, two specific phenotypes of CHD. Maternal diabetes is linked to changes in DNA methylation, and abnormal DNA methylation increases risk of CHD [16].

3.4. Hyperglycemia in Oxidative Stress

The generation and accumulation of ROS induces oxidative stress, which T1DM may cause as it increases superoxide and lipid peroxidation levels in the embryonic heart. Overexpression of superoxide dismutase 1 (SOD1), an antioxidant enzyme, was shown to reduce oxidative stress and alleviate the risk of CHD in mice offspring. An investigation published in 2016 demonstrated that embryonic heart defects were induced by T2DM in offspring of dams, and heightened superoxide levels in embryonic hearts from diabetic dams indicates the participation of oxidative stress in T2DM-induced CHD [18].

Several pathways involving oxidative stress are parallel to the inhibition of CNCC migration leading to apoptosis in developing cardiac tissue. Through murine models, it was shown that, compared to nondiabetic control dams, T2DM protein levels of cleaved caspase 3 and 8, and apoptotic cells in the endocardial cushion, ventricular myocardium, and outflow tract, were significantly more abundant in the embryonic hearts from diabetic dams [18].

4. Clinical Implications and Risk Stratification

As the mechanisms of apoptosis driven by oxidative stress, epigenetic disruption, and reduced cardiac neural crest cell abundance described above are driven by hyperglycemia, logically, the risk of CHD should rise with increase of maternal glycemic levels. In accordance with this, evidence shows that the risk of CHD begins rising when the maternal periconceptional glycated hemoglobin (HbA1c) level exceeds the threshold of 5.6%, found from a large study including 46,534 Israeli births in 2001-2020, and this association between HbA1c and CHD was higher for mothers with T2DM than other forms of diabetes. The risk of CHD remained greater for mothers with T2DM than mothers without pre-existing diabetes even with high adherence to antidiabetic medications [19]. This 5.6% figure falls below even the minimum threshold criteria for prediabetes, let alone true diabetes, according to the guidelines set this year by the American Diabetes Association (ADA), which defines prediabetes by an HbA1c level of 5.7-6.4% [20]. Increasing 1% in HbA1c from the 5.6% threshold showed a 10% increase in risk of CHD for offspring of non-diabetic mothers and a 15% increase for offspring of mothers with T2DM [19].

As cardiac septation is complete by the 7^th week of gestation and CNCC migration and differentiation occur before then, beginning during gastrulation (reference Section 3), it is imperative to control glycemia levels before conception. This measure is especially urgent when considering that although, according to 2016 PRAMS datasets, about 77% of women initiate prenatal care in the first trimester, the average time of the first prenatal care appointment was around 9.3 weeks of gestation [5], which is well after the critical periods of heart development, and first trimester prenatal care has declined from 78.3% to 75.5%, from 2021 to 2024. Additionally, the percentage of pregnancies that received late or no care increased from 6.3% in 2021 to 7.3% in 2024 [21].

5. Preconception Care and Screening

As the window for hyperglycemia and/or type 1 or type 2 pregestational diabetes to disrupt cardiac formation in the fetus closes early in gestation, in some cases before pregnancy is confirmed [5], the only reliable point of prevention of CHD in this aspect is before conception. PCC could lower HbA1c by about 1.27% in the first trimester of pregnancy, according to a collection of 24 studies including 4927 women, and the RR of congenital malformations in offspring whose mothers receives PCC was 0.29, according to a collection of 36 studies, showing that risk reduces by about 71% [22]. While this PCC effectiveness covers congenital malformations in general, there is limited evidence on the influence of PCC on CHD as a specific type of defect. The PCC components may contribute to reduce risk of CHD, though to varying degrees of effectiveness or clarity in mechanisms.

Insulin intake is a preferred therapy for glycemic control, as a 2020 paper reviews multiple cohort studies in which following an intensive insulin therapy regimen, self-monitoring blood glucose levels, taking multiple daily insulin injections, and/or using continuous subcutaneous insulin infusion was associated with lower HbA1c levels and/or lower instances of congenital malformations [22].

Contraception until achieving optimal glycemic control is advised, in order to ensure conception does not occur until diabetic complications are evaluated and stabilized [23].

Weight optimization and active, healthy lifestyle prior to attempting conception can decrease risk of congenital malformation. Maternal obesity is significantly associated with fetal CHD, with adjusted RR 1.44 (1.27-1.63) [24]. One aspect of the preconception lifestyle is avoidance of high caffeine levels, which is teratogenic in animal studies and easily crosses the placenta to reach the fetus in humans. Maternal intake of coffee, though not tea, was insignificantly associated with slight elevation in risk of cardiovascular malformation in a 2006 review, with OR 1.10 (95% CI 0.90-1.50) [25]. In this component, the father takes on the responsibility to maintain physical activity and a controlled lifestyle. Recreational physical activity in the periconception period, including preconception, was associated with a significant reduction in risk of offspring CHD, with OR 0.531 (95% CI 0.301-0.936), and additional hours of parental sitting time above the average of four hours increases the risk of offspring CHD by 0.4%. These findings are supported by evidence that paternal physical activity before conception affects DNA methylations, micro RNAs, and histone and chromatin modifications that modulate the epigenome of the sperm. This parental epigenetic effect of offspring cardiac development was observed in rat models, as trained fathers had increased levels of antioxidant proteins involved in left ventricular homeostasis and transcription regulation compared to sedentary fathers. Additionally, parental smoking seems to increase risk of offspring CHD, with OR 1.56 (95% CI 0.86-2.80) [26,27]. Maternal nutrition control is advised for PCC in diabetic women in general [23,28], though a 2022 systematic review of observational studies concluded that the existing literature did not provide conclusive evidence for increase of risk of fetal CHD due to maternal micronutrient deficiencies [29]. Women with diabetes are advised to achieve a healthy body mass index, on average below 25 kg/m², before conception [23].

Preconception screening and treatment of diabetes complications is essential for pre-existing diabetes. Proliferative retinopathy may be accelerated by pregnancy. In order to continue safe control of glucose, this screening measure should be implemented [23].

Drug safety is essential in the preconception period. The following drugs should be discontinued prior to conception due to teratogenic abilities or insufficient evidence of safety: ACE inhibitors, ARBs, statins, metformin (depending on individual circumstances), SGLT2 inhibitors, and GLP-1 receptor antagonists [23].

Folic acid supplementation is contentiously considered as a possibly PCC measure for reducing the risk of CHD. A 2015 study involving 517,784 births found no significant association between folic acid intake and risk of CHD in the offspring, with adjusted RR of 0.99 (95% CI 0.86-1.13), and an unexpected association of folic acid intake increasing the risk of septal defects, with RR 1.19 (95% CI 1.10-1.30) [30]. However, a 2022 systematic review/meta-analysis that pooled 37 studies found a significant association of decreasing risk of CHD with folic acid supplementation, with RR 0.79 (95% CI 0.71-0.89), though this analysis did not cover the impact of periconceptional folic acid supplementation in developing countries [31]. It is also worthwhile to note that there is consistent and recent evidence supporting the intake of up to 5 mg of folic acid a day to reduce risk of neural tube defects [22,23,28] .

The PCC care described in this review involves multidisciplinary care, possibly involving the aid of various specialists, including obstetricians, endocrinologists, ophthalmologists, dieticians, and diabetes educators [23]. Table 1 summarizes these PCC components below.

6. Discussion: Challenges and Future Directions

Although much evidence supports associations between different factors and risk of CHD, the evidence is all based on observational studies and studies on animal models. Because it is not possible to conduct controlled human experiments regarding risk of hyperglycemia on fetal CHD for ethical reasons, the certainty of causality is limited, though this does not discount the consistent associations discussed in this review.

Gaps exist heavily in implementation of the care described in this review, with lack of equitable healthcare among families of low socioeconomic status or racial and ethnic minorities, who have been shown to have increased risk of death and morbidity from CHD [22,32]. Geographic and financial barriers play roles in decreasing accessibility of comprehensive care for families in rural or remote areas and families with lower income and/or lack of insurance [32]. Disparities in education and literacy levels can also affect achievement of PCC. Health literacy is a positive impactful intervention allowing patients to manage their own behaviors and glycemic control. As patients with high literacy level were 1.85 times more likely to gain diabetes knowledge to control their own conditions than patients who were less educated, demonstrating that the less educated may have lower ability for self-management, which could be a major obstacle to the lifestyle, supplementation, and drug safety recommended for lowering risk of fetal CHD [33].

Beyond walls standing against implementation, uncertainty remains due to evidence from a study involving Mendelian randomization, which has indicated that CHD risk associated with maternal diabetes may depend on separate factors besides glycemic control, such as lipids that induce oxidative stress, inflammation, or endothelial dysfunction early in embryonic development [34]. Greater understanding of these lipid level influences and the independent effects of hyperglycemia, insulin resistance, and metabolism in obesity remains a gap to be explored for prevention strategies targeting CHD etiology [35]. Furthermore, this topic should be further substantiated through more granular analyses of continuous monitoring of glycemic data rather than one-time measurements of HbA1c levels, in order to identify the particular teratogenic risks of glycemic dysregulation through the periconception period [36]. As seen from Section 5, isolating the distinct risk of fetal CHD from the general net of congenital defects remains a necessary task for future research to accomplish.

7. Conclusion

Maternal hyperglycemia disrupts fetal cardiac formation through several mechanisms: apoptosis through oxidative stress, loss of cardiac neural crest cells, and epigenetic dysregulation. These mechanisms of diabetic embryopathy occur in the window of the first seven weeks of gestation, during cardiogenesis, before the heart is largely formed. CHD risk increases even when HbA1c levels are below the standard definition for prediabetes, and this teratogenic window closes early in pregnancy, often before any substantive measures for CHD prevention are able to be carried out, so PCC is crucial for preventive care of CHD. Structured preconception care involving glycemic control, contraception, weight optimization and controlled lifestyle, preconception screening, drug safety, and folic acid supplementation can offer the most direct intervention for reducing CHD risk. Still, the evidence defining distinct CHD risk outcomes is limited, and challenges in experimental studies and inequity for socioeconomically challenged families require further investigation to close gaps in access to PCC and understanding of glycemic and other factors to risk of offspring CHD.