High Risk of Chd in Babies of Obese African American Pregnant Women

Amongst anatomical malformations present at nativity, congenital heart illness (CHD) is the about common, occurring in 0.viii% to 1% of live‐built-in infants, and is increasing in prevalence worldwide.¹ In the current practice of neonatal and pediatric cardiothoracic surgery and perioperative care, the survival of children with CHD approaches 95% to 99% depending on the severity of illness.ⁱⁱ Notwithstanding, childhood survivors of CHD are impacted by neurodevelopmental differences,ⁱⁱⁱ whereas developed survivors of CHD are burdened with adult‐onset cardiovascular disease,^four neuropsychiatric disease,⁵ and cancer.⁶ From infancy through machismo, CHD continues to be an important and increasing proportion of the population at increased risk of morbidity and mortality.

Although the by decade has seen advances in our agreement of the genetic basis of CHD,⁷ maternal diabetes mellitus occurring during early pregnancy has been recognized as a risk factor for disease for many decades.^viii More recently, population‐based observations take described associations between gamble of CHD in the offspring with other maternal cardiometabolic disorders such as obesity.⁹ The significant phenotypic overlap between diabetes mellitus, obesity, and cardiometabolic risk is complex; it is non withal established which of these factors is causal for hazard to the fetus when present in the female parent during early pregnancy (Effigy).

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Effigy 1. Potential mechanisms for transmission of maternal metabolic take a chance for built heart disease (CHD) in the fetus.

Analogy of potential mechanisms of transmission of maternal factors during pregnancy influencing risk for CHD in offspring. Maternal diabetes mellitus and obesity share a multifariousness of intermediate phenotypes (bidirectional gray arrow), which could exist transmissible from mother to fetus in the claret across the placenta (red pointer) or transmitted genetically at the time of conception past pleiotropic variants, conferring risk for both metabolic phenotypes and CHD (dark-green arrow). Specific differences in placental function related to maternal obesity may also contribute to risk (purple pointer). Experimental models have suggested a variety of potential mechanisms by which maternal metabolic factors may disturb development of the heart, which occurs early in pregnancy during the first trimester.

Full general Human relationship: Maternal Obesity

Mirroring trends in the general population, both the rate and severity of maternal obesity has increased at an alarming rate during recent years.¹⁰ In European countries, 7% to 25% of expectant mothers are overweight,¹¹ and in the The states only 45% of mothers have a normal weight when condign pregnant.¹⁰

Maternal obesity is associated with adverse pregnancy outcomes, neonatal complications, and morbidity. These include stillbirth,¹² macrosomia,^{xiii , 14} shoulder dystocia,^fourteen preterm delivery,^fifteen and built malformations, such equally neural tube defects,^{16 , 17} omphalocele,^{17 , 18}and CHD.^{17 , 18 , 19 , xx , 21 , 22} Moreover, a dose‐dependent association has too been observed whereby severity of maternal obesity is directly associated with run a risk for adverse neonatal outcomes.^{nine , 23}

Several contempo meta‐analyses consistently report a full general clan between maternal overweight and obesity and run a risk for congenital heart defects in the offspring.^{24 , 25 , 26} The increased risk associated with maternal obesity includes a broad range of different cardiac defects, including septal defects,^{9 , 22 , 27} aortic curvation defects,⁹ persistent ductus arteriosus,^{9 , 21} conotruncal defects,^{9 , 27 , 28 , 29 , 30} left ventricular outflow tract obstruction defects,²⁹ and right ventricular outflow tract defects.^{21 , 28} The association of take chances regarding specific CHD subtypes, withal, has not been universally consistent in different studies. I source of bias could be the fact that body mass index (BMI) estimations in many of these studies were based on retrospective of cocky‐reported data, which are associated with recall bias. In addition, many of the studies report only prenatally or neonatally diagnosed defects. Given that noncritical CHD may non cause symptoms at birth and diagnosed later in life, these studies might be under‐reporting CHD rates. Finally, many of the studies are case‐control studies, which provide estimates of risk that may exist less reliable than prospective, population‐based cohort studies for estimating prevalence.

The largest single study thus far, including a national cohort of 2 050 491 live‐built-in singleton infants in Sweden, showed that maternal obesity measured at the first antenatal visit increased the risk to offspring for transposition of not bad arteries in those with a BMI of 35 to 40 and >40 kg/m², aortic arch defects in those with a BMI of 30 to 35, 35 to forty, and >40 kg/m^two, single‐ventricle eye in a group of mothers with a BMI of 30 to 35 kg/one thousand^two, and atrial septal defect and patent ductus arteriosus in mothers with a BMI of >25 kg/thousand². In improver, the risk for pulmonary valve defects was increased in offspring of mothers with a BMI of xxx to 35 kg/yardⁱⁱ.^ix The strengths of this written report included a population‐based design with prospectively collected data on both exposure and outcome in a country with publicly funded health care, but did non accept into account pregnancies with CHD that resulted in termination or stillbirth.

The risk for CHD besides appears to increment with the severity of obesity. The study by Persson et al from Sweden demonstrated that the risk for built malformations, including CHD, progressively increased with BMI from overweight to severe obesity.³¹ When focusing on specific CHD groups, aortic arch defects, atrial septal defect, and patent ductus arteriosus presented with a dose‐responsive association.^ix In addition, a similar dose‐responsive association has been reported in hypoplastic left middle syndrome and right outflow tract defects.²¹

Potential Mechanisms of Adventure in Maternal Obesity

The precise mechanism by which maternal obesity impacts critical stages of cardiac development is not known and is hypothesized to exist multifactorial. Whereas the mechanisms of maternal obesity in afterward gestation on placental role and fetal growth take been under agile research during contempo years, early pregnancy has received less attention.

Maternal prepregnancy obesity is known to be associated with increased risk for gestational diabetes mellitus,³² and information technology is probable that some of the effect in obese individuals may be mediated past glycemic dysregulation. Yet, the CHD‐risk increment has remained pregnant even afterward adjusting for glucose levels, suggesting that abnormalities in glucose metabolism do not fully explain the gamble in obese mothers.²⁷ In addition to glycemic dysregulation, a wide range of metabolic abnormalities are present in obese individuals. Obesity is associated with hyperinsulinemia and insulin resistance,^{33 , 34} dyslipidemia,^{33 , 35} and oxidative stress.³⁵ In pregnancy, gestational diabetes mellitus increases low‐density lipoprotein susceptibility to oxidation, and obesity has been farther shown to exacerbate this consequence.³⁶ Compared with nonobese women, obese mothers may display differential fatty distribution, where nonobese women accumulate fat in the lower torso whereas obese women accrue fatty in the upper body.³⁷ Upper‐trunk obesity is associated with reduced uptake and storage of fatty acids, along with increases in lipolysis.³⁸ In dissimilarity, lower‐trunk fat accumulation is associated with more than‐favorable lipid and carbohydrate metabolic dysregulation³⁹ and an overall lower‐adventure metabolic profile.⁴⁰ Thus, the potential negative effects of adverse metabolic changes related to fat accumulation during pregnancy are more than profound in obese individuals, which may contribute to increased levels of adverse effects in the fetus.

Fetal macrosomia associated with maternal obesity has been proposed to ascend from an increased placental food transfer, related, at least partly, to adiponectin levels. Circulating adiponectin levels are lower in obese individuals⁴¹ and remain lower in obese individuals throughout pregnancy.⁴² Lower adiponectin levels during pregnancy have been associated with placental insulin resistance^{43 , 44} and adverse placental part, in terms of increased placental nutrient transfer^{45 , 46 , 47} and increased fetal growth.⁴⁸ Evolution of the pancreas and product of insulin do not occur until the beginning of the second trimester; therefore, during the menses of heart evolution during the early first trimester, the fetus is unable to regulate glucose and may be susceptible to adiponectin‐related dysfunction in placental glucose transport.⁴⁹

Endothelial cell dysfunction in mice lacking endothelial nitric oxide synthase during embryogenesis has been shown to cause CHD in mice.^{50 , 51} Obesity causes chronic pre‐existing endothelial activation and impairment of endothelial function,^{33 , 52 , 53 , 54} every bit well as inflammatory upregulation.³³ Bioavailability of nitric oxide, a regulator of vascular tone, is decreased in endothelial cell dysfunction. Insulin⁵⁵ and adiponectin⁵⁶ actuate endothelial nitric oxide synthase, whereas in obesity and diabetes mellitus these protective mechanisms are diminished. Maternal obesity is associated with increased abnormalities in placental vascular supply, and it has been shown to have an adverse result on fetal vascular circulation.⁵⁷ Thus, the endothelial dysregulation present in obese mothers may extend to the fetal circulation to impact developmental pathways in the fetus. Moreover, the upshot may persist afterward birth, given that it has been observed that offspring of nonhuman primates exposed to a high‐fat diet during pregnancy have impaired endothelial office >1 year after birth.⁵⁸

Finally, it has been proposed that some of the CHD chance increase is mediated by a lower diagnostic rate in pregnancy screenings in obese individuals, given that cardiac views during pregnancy are suboptimal in obese mothers. Decreased sensitivity of ultrasound for cardiac anatomy has been documented in obese mothers.^{59 , 60 , 61} Whereas rates of pregnancy termination are difficult to define and compare between studies, it is possible that differences in diagnostic rates could affect termination rates, leading to a higher share of CHD pregnancies carried to birth in obese mothers with lower diagnostic rates. Nevertheless, in a recent study of an advanced nation‐wide CHD screening plan inside a country with universal wellness coverage, obesity or other maternal hazard factors for offspring astringent centre disease did not announced to affect prenatal detection equally such.^thirty

Touch of Handling and Prenatal Intendance

Lifestyle interventions aiming to restrict weight gain in obese women during pregnancy are seen as a means to reduce adverse outcomes related to obesity. A healthier nutrition during the year before pregnancy has been shown to decrease the take chances for conotruncal and septal defects in the offspring,⁶² and one‐carbon‐rich dietary pattern during pregnancy, characterized by a loftier intake of fish and seafood, has been associated with a reduced run a risk of overall CHD.⁶³ Maternal malnutrition and especially folate deficiency has been associated with CHD in the offspring,⁶⁴ and there is show that obese mothers may have an insufficient response to folic acrid supplementation for primary prevention of congenital anomalies.^{65 , 66} Lifestyle interventions for expectant mothers with obesity and/or previous gestational diabetes mellitus during pregnancy have not, nonetheless, resulted in an consequence on gestational weight proceeds, or obstetric or perinatal outcomes.⁶⁷ It has been suggested that obesity could be associated with a lower compliance for following nutritional recommendations.⁶⁸ Moreover, prepregnancy BMI is a stronger predictor for adverse outcomes as compared with gestational weight gain.⁶⁹ These results indicate that lifestyle interventions should be increasingly aimed at mothers planning pregnancy. Interestingly, certain genetic risk variants have been shown to modify the effectiveness of lifestyle interventions,^seventy which might touch on targeting of such interventions in the futurity.

Several beast studies take addressed interventions to better the outcome of obese pregnancies. Exercise has been shown to prevent adverse effects of maternal obesity on placental vascularization and fetal growth.⁷¹ In a mouse model, exercise in obese pregnancy was benign to offspring cardiac function and structure.⁷² Adiponectin levels are lower in obese mothers, and adiponectin supplementation of mice during late pregnancy reversed the adverse furnishings of maternal obesity on placental function and fetal growth.^{73 , 74} Moreover, although these interventions showed to be beneficial in terms of maternal and fetal wellness, none of these studies specifically addressed CHD equally an result.

General Relationship: Glycemic Regulation

The association between maternal diabetes mellitus and CHD in offspring has been recognized for almost 80 years.⁸ The underlying pathology of diabetes mellitus is a mismatch between insulin production and response to insulin resulting in elevated glucose levels. Type i diabetes mellitus is attributable primarily to the absenteeism of pancreatic insulin secretion originating from autoimmune destruction of beta cells. Type 2 and gestational diabetes mellitus arise from an increased requirement for insulin for intracellular ship of glucose in peripheral tissues, a at present well‐described physiological miracle of insulin resistance implicated in the pathophysiology of a variety of developed‐onset diseases.⁷⁵ Maternal diabetes mellitus is a risk factor for adverse maternal and fetal outcomes, including anatomical malformations such every bit CHD.^{76 , 77} Chance for CHD in offspring is present in mothers with all types of affliction, such as blazon one^{78 , 79} or ii^{79 , 80} diabetes mellitus existing before pregnancy, along with gestational diabetes mellitus developing during pregnancy.^{81 , 82}

In large, population‐based studies, maternal diabetes mellitus appears to exist a potent risk cistron for any and all subtypes of CHD.^{81 , 83} Private studies hint at a higher risk for conotruncal and laterality subtypes of CHD^{83 , 84}; however, comparisons between subtypes are limited by low prevalence of individual malformations nowadays even in big cohorts. For syndromic causes of CHD with a known genetic etiology, such equally Down syndrome, maternal diabetes mellitus is not recognized as a cofactor for cardiac malformation in the fetus.⁸⁵ On a population level, exposure to prepregnancy diabetes mellitus was estimated to be responsible for upwards to four.2% of CHD inside a regional Canadian wellness system.^eighty

Cardiac development occurs during the commencement trimester and is largely complete by the sixth week of pregnancy; thus, maternal physiology and metabolism during the early on start trimester is nearly relevant to the developing fetal middle. Hemoglobin A1C values measured during the beginning trimester are associated with gamble for CHD in offspring,^{86 , 87} and women with pre‐existing diabetes mellitus who experienced a greater number of diabetic complications or had a greater hemoglobin A1C appear to be at increased risk of having a child with CHD.^{78 , 83} Our own contempo data suggest that risk for CHD extends to pregnancies of women who may not carry a clinical diagnosis of diabetes mellitus; abnormalities of glucose metabolism beneath standard diagnostic thresholds for diabetes mellitus are associated with measurable take a chance for CHD in offspring.^{88 , 89} Thus, risk of CHD in offspring is directly correlated with abnormalities in glucose metabolism in pregnancies with and without diabetes mellitus.

Mechanism of Risk

The mechanism by which presence of maternal diabetes mellitus during disquisitional stages of cardiac evolution is not articulate. The earliest experiments simply treated craven and rodent embryos with exogenous glucose, which resulted in malformations in many organ systems including cardiac defects.^{90 , 91} Experimentally supported mechanisms proposed to alter cardiac evolution include glucose‐mediated disturbances of left‐right patterning,⁹² increased apoptosis resulting from oxidative or other cellular stress,^{93 , 94} deficiencies in nitric oxide signaling,⁹⁵ dumb autophagy,⁹⁶ and alterations of neural crest cell formation and migration.^{97 , 98} Deriving from early descriptions of the teratogenic potential of glucose solitary, ex vivo models of cardiac evolution have substituted treatment with supraphysiological levels of glucose as a proxy for maternal diabetes mellitus. However, alterations in maternal glucose are accompanied by changes in downstream metabolites of glycolysis, such as beta‐hydroyxbutyrate,⁹⁹ and the impact of downstream metabolites of glucose upon cardiac evolution remains relatively unexplored.^{100 , 101 , 102} Accompanying these mechanistic hypotheses, experimental models of maternal diabetes mellitus take also described the disruption of canonical signaling pathways during mesodermal differentiation and cardiac development.¹⁰³ The variety of proposed cellular models and molecular mechanisms, none of which are mutually exclusive, highlights the need for further enquiry into how maternal diabetes mellitus disturbs fetal middle development (Figure).

Impact of Treatment and Prenatal Intendance

Like maternal obesity, maternal diabetes mellitus is associated with a variety of adverse pregnancy outcomes, including pre‐eclampsia, prematurity, fetal demise, and stillbirth.⁷⁷ These outcomes accept prompted public health efforts to ameliorate preconception and prenatal diagnosis and treatment for diabetes mellitus. In a meta‐analysis studying prenatal care, standard treatment of maternal diabetes mellitus resulted in ~75% reduction in gamble of anatomical malformations in offspring inclusive of CHD.¹⁰⁴ Newer technological approaches to diabetes mellitus care, including continuous glucose monitoring and continuous subcutaneous insulin injection, are in common use by women of childbearing age,¹⁰⁵ and randomized controlled trials using these technologies demonstrate incremental improvements in measures of glucose control and improvements in some measures of pregnancy and fetal issue.¹⁰⁶ Simulations suggest that in the U.s.a. population, achieving glycemic control in all women before pregnancy has the potential to reduce rates of CHD by 3.8% or 2670 cases per twelvemonth.¹⁰⁷

In improver to standard care of diabetes mellitus before and during pregnancy, other routine interventions have been trialed in pregnant women with maternal diabetes mellitus with the goal of preventing adverse fetal and maternal outcomes. Exercise during pregnancy is prophylactic and reduces maternal glucose levels,¹⁰⁸ merely in that location is inadequate bear witness to assess any impact of maternal practice on fetal outcomes.¹⁰⁹ Trials to approximate the bear on of dietary interventions during pregnancy upon maternal and fetal outcomes are ongoing.¹¹⁰ Conversely, observational studies suggest that exposure to either metformin or beta‐blockers during pregnancy, both of which reduce glucose levels, may actually increase the chance of sure types of CHD in the fetus.^{111 , 112} In summary, routine adjunctive interventions targeted at glucose reduction in maternal diabetes mellitus have yet to demonstrate improvements in fetal outcomes, such equally CHD, in appropriately controlled trials.

Novel interventions centered on proposed mechanisms of illness have arisen from experimental animate being models of maternal diabetes mellitus. Pharmacological agents, which better oxidative stress, take been reported to forestall cardiac malformations; in a chick model of maternal diabetes mellitus, coinjection of N‐acetyl cysteine with glucose prevented heart malformations acquired by injection of glucose lone.¹¹³ In a mouse model of blazon one diabetes mellitus, neural tube defects (as well associated with maternal diabetes mellitus) were prevented by maternal ingestion of trehalose, a polysaccharide with antioxidant properties.¹¹⁴ Nitric oxide is a key vascular signaling molecule synthesized in the smooth musculus and endothelium, which is disturbed in diabetes mellitus¹¹⁵; oral supplementation of diabetic mice with a cofactor for nitric oxide synthase reduced the rates of CHD in offspring.⁹⁵ Withal, given the observation that fifty-fifty clinically accepted interventions to reduce maternal glucose fail to impact the charge per unit of fetal malformations during pregnancy and an absence of consensus on the machinery of gamble, the prospect of prenatal interventions derived from experimental beast models should be viewed with caution.

Knowledge Gaps and Time to come Directions

CHD causes high levels of physical, emotional, and economical burden for the patient, their family, and society at large. Although maternal obesity and glucose metabolism are clearly associated with the hazard of CHD, the mechanisms by which risk is transmitted from female parent to fetus and the causal factors which disturb fetal cardiac development remain poorly defined (Effigy). Understanding the causal factors and mechanism of transmission will provide the necessary framework for addressing 2 of import real‐world outcomes; primary prevention of CHD and improving prenatal screening for CHD.

Given that neonatal and childhood surgery are likely to exist the mainstay of handling for the foreseeable future, and that cardiopulmonary bypass and perioperative disturbances in physiology may contribute to the agin health outcomes in long‐term survivors of CHD,^{116 , 117} principal prevention of affliction is an important goal with potentially pregnant do good to public health. Obesity and diabetes mellitus are both potentially modifiable maternal hazard factors for CHD, each with effective evidence‐based therapies generally and in the context of maternal wellness.^{118 , 119} With a clear understanding of the mechanism of risk transmission from mother to fetus, large‐calibration trials of public health interventions focused upon causal factors underlying maternal obesity and glucose metabolism with specific attending to fetal outcomes are needed. Where possible, fetal outcomes data inclusive of cardiac malformations should be scrutinized from ongoing trials of dietary interventions¹¹⁰ and innovations in glucose control¹⁰⁶ in order to guide efforts prospective interventions for CHD. Lifestyle factors, such equally weight, physical activity, and dietary habits, correspond potential targets for preconception and prenatal interventions for CHD prevention.

A central component of prenatal care is the in utero identification of pregnancies with CHD equally early as possible. An improved understanding of the maternal risk factors for carrying a pregnancy impacted by CHD holds the potential to better both prenatal screening and postnatal care. Improved risk stratification of significant women may allow for meliorate selection of pregnancies at the greatest take chances of CHD for prenatal screening by fetal echocardiogram,¹²⁰ particularly in health systems with less‐organized screening programs.^{xxx , 121} In pregnancies with CHD which are carried to term,¹²² prenatal detection besides allows early referral to a third center to optimize the delivery and early care, and thus improved prenatal screening is likely to improve early survival and long‐term outcomes of children afflicted with CHD.^{123 , 124}

Although the significance of maternal glucose metabolism and obesity as take a chance factors for CHD is clear, the mechanisms underlying these risks are not. A deep mechanistic agreement of causal maternal factors holds the potential to meliorate both prevention of CHD past preconception and prenatal treatment of causal maternal factors, and to amend prenatal screening and in utero identification of CHD past measuring causal maternal factors to identify pregnancies at highest chance. The molecular mechanisms of maternal run a risk and potential genetic modifiers of these factors stand for an outstanding opportunity where advances from bones, translational, and clinical inquiry are poised to yield real‐world applications to reduce the burden of disease.

Disclosures

None.

Footnotes

*Correspondence to: James R. Priest, MD, Section of Pediatrics (Cardiology), Stanford University School of Medicine, 750 Welch Rd, Ste 325, Palo Alto, CA 94304. East‐post: [email protected] edu

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