The association between maternal air pollution exposure and the incidence of congenital heart diseases in children: A systematic review and meta-analysis.

Congenital heart diseases (CHDs) are a prevalent form of congenital malformations in newborns. Although previous studies have explored the association between maternal exposure to ambient air pollution and congenital anomalies in offspring, the results still remain ambiguous. To fill the knowledge gap, we performed a systematic review and meta-analysis of existing literature. A comprehensive search of the literature was conducted in PubMed, Embase, and Web of Science until August 12, 2022. We analyzed the relationship between air pollution and multiple CHDs using either a fixed-effect model or a random-effects model. Summary risk estimates of pollution-outcome pairs were calculated based on (i) risk per increment of concentration and (ii) risk at high versus low exposure levels. Additionally, we performed leave-one-out analyses and used funnel plots to assess the potential publication bias. A total of 32 studies were included and four studies utilizing distributed lag nonlinear models (DLNM) models were added to our retrospective review. In the continuous exposure meta-analysis, there were statistically significant negative associations between sulfur dioxide (SO2) and transposition of the great arteries (OR = 0.96; 95 % CI: 0.93-0.99), pulmonary artery and valve defect (OR = 0.90; 95 % CI: 0.83-0.97), and ventricular septal defect (OR = 0.95; 95 % CI: 0.91-0.99). High versus low SO2 exposure was associated with a decreased risk of tetralogy of Fallot [OR = 0.83; 95 % CI: 0.69-0.99]. However, carbon monoxide (CO) increased risk estimates for tetralogy of Fallot in both continuous exposure (OR = 2.25; 95 % CI: 1.42-3.56) and high-low exposure (OR = 1.24; 95 % CI: 1.01-1.54). Particulate matter 10 (PM10) statistically significant increased in the risk of overall CHD with odds ratios of 1.03 (95 % CI: 1.01-1.05) and 1.04 (95 % CI: 1.00-1.09) in continuous and categorical exposure analysis, respectively. These findings provide potential evidence for the association between maternal air pollution exposure and CHDs.

The association between natural gas well activity and specific congenital anomalies in Oklahoma, 1997-2009.

BACKGROUND: Natural gas drilling may pose multiple health risks, including congenital anomalies, through air pollutant emissions and contaminated water. Two recent studies have evaluated the relationship between natural gas activity and congenital anomalies, with both observing a positive relationship. OBJECTIVES: We aimed to evaluate whether residence near natural gas wells is associated with critical congenital heart defects (CCHD), neural tube defects (NTD), and oral clefts in Oklahoma, the third highest natural gas producing state in the US. METHODS: We conducted a retrospective cohort study among singleton births in Oklahoma (n = 476,600) to evaluate natural gas activity and congenital anomalies. We calculated an inverse distance-squared weighted (IDW) score based on the number of actively producing wells within a two-mile radius of the maternal residence during the month of delivery. We used modified Poisson regression with robust error variance to estimate prevalence proportion ratios (PPR) and 95% confidence intervals (CI) for the association between tertiles of natural gas activity (compared to no wells) and CCHD, NTD, and oral clefts adjusted for maternal education. RESULTS: We observed an increased, though imprecise, prevalence of NTDs among children with natural gas activity compared to children with no wells (2nd tertile PPR: 1.34, 95% CI: 0.93, 1.93; 3rd tertile PPR: 1.20, 95% CI: 0.82, 1.75). We observed no association with CCHD or oral clefts overall. Specific CCHDs of common truncus, transposition of the great arteries, pulmonary valve atresia and stenosis, tricuspid valve atresia and stenosis, interrupted aortic arch, and total anomalous pulmonary venous connection were increased among those living in areas with natural gas activity compared to those living in areas without activity, though not statistically significant. DISCUSSION: Our results were similar to previous studies for NTDs and specific CCHDs. Future directions include evaluating the association between specific phases of the drilling process and congenital anomalies to better refine the relevant exposure period.

Congenital diaphragmatic hernia after exposure to a triple retinoic acid antagonist during pregnancy.

AIM: To establish a mouse model for the study of congenital defects, using exposure of pregnant females to the teratogen BMS-189453, a multiple retinoic acid competitive antagonist.We found not less than 60% of fetuses had transposition of the great arteries and l5% had other congenital heart defects such as double outlet right ventricle, tetralogy of Fallot, truncus and right aortic arch. Newborns exposed in utero to BMS-189453 were affected by thymus aplasia or hypoplasia, and severe congenital anomalies of the central nervous system due to neural tube defects. An anterior rotation of the right lung was also frequently present in our model. We also report a case of murine congenital diaphragmatic hernia associated with thymic aplasia and transposition of the great arteries. CONCLUSION: These findings support the hypothesis that the combination of diaphragmatic hernia and congenital heart defects may be related to an alteration of the retinoic acid signaling pathways.

Impaired development of left anterior heart field by ectopic retinoic acid causes transposition of the great arteries.

BACKGROUND: Transposition of the great arteries is one of the most commonly diagnosed conotruncal heart defects at birth, but its etiology is largely unknown. The anterior heart field (AHF) that resides in the anterior pharyngeal arches contributes to conotruncal development, during which heart progenitors that originated from the left and right AHF migrate to form distinct conotruncal regions. The aim of this study is to identify abnormal AHF development that causes the morphology of transposition of the great arteries. METHODS AND RESULTS: We placed a retinoic acid-soaked bead on the left or the right or on both sides of the AHF of stage 12 to 14 chick embryos and examined the conotruncal heart defect at stage 34. Transposition of the great arteries was diagnosed at high incidence in embryos for which a retinoic acid-soaked bead had been placed in the left AHF at stage 12. Fluorescent dye tracing showed that AHF exposed to retinoic acid failed to contribute to conotruncus development. FGF8 and Isl1 expression were downregulated in retinoic acid-exposed AHF, and differentiation and expansion of cardiomyocytes were suppressed in cultured AHF in medium supplemented with retinoic acid. CONCLUSIONS: The left AHF at the early looped heart stage, corresponding to Carnegie stages 10 to 11 (28 to 29 days after fertilization) in human embryos, is the region of the impediment that causes the morphology of transposition of the great arteries.

Congenitally corrected transposition of the great arteries in a patient with cor triatriatum: a rare combination.

Congenitally corrected transposition of the great arteries is a rare anomaly that is thought to arise from a defect in looping of the primitive cardiac tube. Cor triatriatum is another rare congenital cardiac anomaly due to faulty incorporation of the common pulmonary vein into the left atrium. We present a rare case comprising both disorders in one patient.

A multiple retinoic acid antagonist induces conotruncal anomalies, including transposition of the great arteries, in mice.

BACKGROUND: The morphogenetic mechanisms that are responsible for the transposition of the great arteries are still largely unknown, mainly because this malformation is very difficult to experimentally reproduce. The aim of the present study was to test the effect of BMS-189453, a retinoic acid antagonist, on murine heart morphogenesis. METHODS: We administered this drug at 5 mg/kg body weight (twice, at a 12-h interval) to pregnant mice on 6.25/6.75 days postcoitum (dpc) (Group A), 6.75/7.25 dpc (Group B), 7.25/7.75 dpc (Group C), 7.75/8.25 dpc (Group D), or 8.25/8.75 dpc (Group E). At birth, the anatomical features of fetuses were evaluated by stereomicroscopic examination. RESULTS: In Group A (18 fetuses), cardiovascular anatomy was normal in 10 (56%) cases, and 8 (44%) fetuses presented with transposition of the great arteries. In Group B, no fetuses were obtained. In Group C (78 fetuses), cardiovascular anatomy was normal in 19 (24%) cases, while 59 (76%) mice presented with various types of cardiac defects, including 48 transpositions of the great arteries (61%). In Group D (80 fetuses), cardiac defects were seen in 22 (27%) mice: 14 of these (17%) were transpositions of the great arteries. In Group E (72 fetuses), cardiovascular anatomy was normal in all cases. Of 248 fetuses analyzed, 87% presented with thymic aplasia or hypoplasia, and 20% presented with meroanencephalia and/or rachischisis. CONCLUSIONS: Transposition of the great arteries can be consistently reproduced in mice by administration of a retinoic acid competitive antagonist on 7.5 dpc.

Coronary artery embryogenesis in cardiac defects induced by retinoic acid in mice.

BACKGROUND: Although normal coronary artery embryogenesis is well described in the literature, little is known about the development of coronary vessels in abnormal hearts. METHODS: We used an animal model of retinoic acid (RA)-evoked outflow tract malformations (e.g., double outlet right ventricle [DORV], transposition of the great arteries [TGA], and common truncus arteriosus [CTA]) to study the embryogenesis of coronary arteries using endothelial cell markers (anti-PECAM-1 antibodies and Griffonia simplicifolia I (GSI) lectin). These markers were applied to serial sections of staged mouse hearts to demonstrate the location of coronary artery primordia. RESULTS: In malformations with a dextropositioned aorta, the shape of the peritruncal plexus, from which the coronary arteries develop, differed from that of control hearts. This difference in the shape of the early capillary plexus in the control and RA-treated hearts depends on the position of the aorta relative to the pulmonary trunk. In both normal and RA-treated hearts, there are several capillary penetrations to each aortic sinus facing the pulmonary trunk, but eventually only 1 coronary artery establishes patency with 1 aortic sinus. CONCLUSIONS: The abnormal location of the vessel primordia induces defective courses of coronary arteries; creates fistulas, a single coronary artery, and dilated vessel lumens; and leaves certain areas of the heart devoid of coronary artery branches. RA-evoked heart malformations may be a useful model for elucidating abnormal patterns of coronary artery development and may shed some light on the angiogenesis of coronary artery formation.

Transposition of the great arteries and hypocalcemia in a patient with fetal hydantoin syndrome.

We report a patient with fetal hydantoin syndrome (FHS) with associated d-transposition of the great arteries (d-TGA) and persistent hypocalcemia. d-TGA and hypocalcemia have each been individually reported once in association with FHS, but these patients were also prenatally exposed to phenobarbital. To our knowledge, this is the first report of these problems occurring after prenatal exposure to hydantoin alone. The combination of congenital heart disease and hypocalcemia in our patient raises the possibility of a hydantoin effect on neural crest migration.

Developmental spectrum of cardiac outflow tract anomalies encompassing transposition of the great arteries and dextroposition of the aorta: pathogenic effect of extrinsic retinoic acid in the mouse embryo.

We previously reported that retinoic acid shows a dose-dependent differential induction of various cardiac outflow anomalies: transposition of the great arteries is induced mainly by a high dose (70 mg/kg) and dextroposition of the aorta by a low dose (40-60 mg/kg; Yasui et al., 1995). We subsequently delineated the aberrant outflow tract septation process leading to the transposition (Yasui et al., 1997). The aim of the present study was to illustrate a spectrum of developmental abnormalities by examining mouse embryos treated with a low dose of retinoic acid and comparing them with embryos administered a high dose. We employed in situ observation on live embryos to discern the blood flow streams and scanning electron microscopy to clarify the internal structure. The embryos treated with a low dose of retinoic acid showed several basic phenotypes common to the high dose retinoic acid group, although variable and relatively mild, such as hypoplasia and dysplasia in the proximal outflow cushions, decreased counter-clockwise rotation in the distal outflow tract, and deviation of the edges of the developing outflow septum. In typical cases, the right-sided edge of the developing outflow septum shifted ventrally by various degrees, allowing for the right ventricle-to-aorta pathway, whereas the left-sided edge preserved the continuity with the interventricular septum, as in the normal embryo. These findings indicate that morphogenesis of dextroposition of the aorta and transposition of the great arteries are not only distinct but also show some basic pathways in common.

Distribution of fibronectin, type I collagen, type IV collagen, and laminin in the cardiac jelly of the mouse embryonic heart with retinoic acid-induced complete transposition of the great arteries.

BACKGROUND: In the mouse model of complete transposition of the great arteries (TGA) produced by all-trans retinoic acid (RA), parietal and septal ridges in the outflow tract (OT) are hypoplastic. At first, these ridges are generated by an expanded cardiac jelly (mainly myocardial basement membrane). Thereafter, endothelial cells delaminate and invade into the adjacent cardiac jelly to form endocardial cushion tissue (formation of cushion ridge). During cushion tissue formation, basement membrane antigens play an important role in the regulation of this endothelial-mesenchymal transformation. METHODS: To examine whether the myocardial basement membrane components are altered in the RA-treated heart OT, immunohistochemistry for fibronectin, type I collagen, type IV collagen, and laminin was carried out in mouse embryonic hearts at 9.5 and 10.5 ED (embryonic day; vaginal plug = day 0) with or without prior exposure to RA. RESULTS: Particulate/fibrillar fibronectin and fibrillar type I collagen were observed in the thick cardiac jelly of the control heart at the onset of mesenchymal formation. In the RA-treated heart, an intermittent patchy staining for fibronectin and a sparse distribution of type I collagen were observed in the thin cardiac jelly. Laminin and type IV collagen were distributed continuously on the basal surface (layer adjacent to the basal plasma membrane) of endocardium and myocardium in both control and RA-treated hearts. CONCLUSIONS: The alterations in the antigens of the myocardial basement membrane (cardiac jelly) may be responsible for the hypoplasticity of parietal and septal ridges that characterizes RA-induced TGA morphology. This may be one of the reasons why mesenchymal cell formation is inhibited in the RA-induced TGA.

Hypoplasia of cushion ridges in the proximal outflow tract elicits formation of a right ventricle-to-aortic route in retinoic acid-induced complete transposition of the great arteries in the mouse: scanning electron microscopic observations of corrosion cast models.

BACKGROUND: The major morphologic change associated with retinoic acid (RA)-induced complete transposition of the great arteries (TGA), a congenital malformation of the heart, was investigated in a mouse model in which TGA was found in 80% of surviving fetuses. METHODS: Corrosion casts of embryonic hearts with or without prior exposure to retinoic acid were observed under a scanning electron microscope. RESULTS: In control hearts, indentations caused by expanded parietal and septal ridges in the outflow tract established right ventricle-to-left ventral pulmonic and left ventricle-to-right dorsal aortic routes before the aorticopulmonary septum completion. In RA-treated hearts, indentations of proximal regions of the parietal and septal ridges were small in the proximal outflow tract, whereas those in the distal regions developed well. These morphological features in the RA-treated hearts elicited right ventricle-to-right ventral aortic and left ventricle-to-left dorsal pulmonic routes in the TGA morphology. CONCLUSIONS: Hypoplasticity of the proximal regions of parietal and septal ridges in the outflow tract is one of the primary morphological abnormalities of the RA-induced TGA.

Inhibition of outflow cushion mesenchyme formation in retinoic acid-induced complete transposition of the great arteries.

OBJECTIVE: Endocardial cushion tissue formation, the primordia of valves and septa, is a critical event in cardiac morphogenesis. Maternally administrated all-trans retinoic acid is known to induce complete transposition of the great arteries (TGA) in the mouse embryo. To address the mechanisms of TGA, the effect of retinoic acid on cushion tissue formation was examined. METHODS: Using a three-dimensional collagen gel culture model, we performed various types of endothelial-mesenchymal transformation assays of co-cultured endocardium with myocardium obtained from 9.5-day mouse embryonic hearts. In vivo immunohistochemical detections of extracellular matrices, fibronectin and type I collagen, were also performed. RESULTS: Endothelial-to-mesenchymal transformation at the onset of cushion tissue formation was suppressed in the outflow tract of embryos exposed to retinoic acid in culture. This inhibitory effect of retinoic acid was spatially restricted to the outflow tract and reversed by treatment with embryonic myocardial conditioned medium enriched in extracellular inductive molecules. Mesenchyme formation in the outflow tract was inhibited at a lower concentration of retinoic acid (10(-10) mol/l) than that which inhibited the atrio-ventricular canal (10(-7) mol/l) in culture. The fibronectin and type I collagen depositions in pre-migratory outflow tract cardiac jelly in retinoic acid-treated embryonic heart were reduced compared to those in the control. CONCLUSIONS: Exogenously applied retinoic acid inhibits outflow tract cushion mesenchyme formation in the embryonic heart with TGA. It is suggested that retinoic acid inhibits the expression of extracellular matrices and inductive molecules synthesized by myocardium in the outflow tract.

Morphological observations on the pathogenetic process of transposition of the great arteries induced by retinoic acid in mice.

BACKGROUND: The pathogenesis of complete transposition of the great arteries (TGA) is still controversial because useful animal models have not been established. We previously reported that all-trans retinoic acid induced complete TGA at a high proportion in mice. The aim of the present study was to clarify the morphogenesis of the cardiac outflow tract in the retinoic acid-treated embryos destined to develop TGA. METHODS AND RESULTS: We first examined the morphology of TGA in mouse fetuses treated with retinoic acid to establish an animal model of TGA (experiment 1) and then examined the retinoic acid-treated embryonic hearts by means of ink injection and histology (experiment 2). All mouse fetuses and embryos showed visceroatrial situs solitus and d-ventricular loop. In experiment 1, among 45 embryos treated with retinoic acid 70 mg/kg at day 8.5 of gestation, 35 (78%) had TGA and 3 (6.7%) had a double-outlet right ventricle with a subpulmonary ventricular septal defect. In experiment 2, all hearts already exhibited d-loop at gestation day 8.5. At gestation day 9.5, conus swellings, composed of acellular cardiac jelly, where hypoplastic, and the conotruncal cavity was nonspiral or tubular. At gestation day 11.0, aberrant conus swellings located anteroposteriorly to give a straight orientation to the conotruncal cavity. At gestation day 12.0, side-by-side great arteries were transposed in that the aorta arose from the right ventricle and the pulmonary artery arose above the interventricular foramen. CONCLUSIONS: These results suggest that a reproducible animal model of TGA can be produced in mice by treatment with retinoic acid; that there was no loop anomaly, such as an A-loop or L-loop, in our model; and that hypoplasia of the conus swellings appears to be the primary event leading to TGA.

The relation of aspirin use during the first trimester of pregnancy to congenital cardiac defects.

It has been hypothesized that the ingestion of aspirin by women during pregnancy increases their infants' risk of certain congenital heart defects. Using data from a large program of case-control surveillance of congenital malformations, we evaluated this hypothesis. The case groups were made up of infants with any structural cardiac defect (n = 1381) and five selected cardiac defects (the subgroups were not mutually exclusive): aortic stenosis (n = 43), coarctation of the aorta (n = 123), hypoplastic left ventricle (n = 98), transposition of the great arteries (n = 210), and conotruncal defects (n = 791). First-trimester aspirin use among the mothers of these infants was compared with that among the mothers of a control group of infants with other malformations (n = 6966). The prevalence of any maternal aspirin use was similar for cases (25 to 33 percent) and controls (27 percent). The relative risks (and 95 percent confidence interval) among infants whose mothers were aspirin users as compared with those whose mothers did not use aspirin, adjusted for potential confounding factors, were 0.9 (0.8 to 1.1) for any cardiac defect, 1.2 (0.6 to 2.3) for aortic stenosis, 1.0 (0.6 to 1.4) for coarctation, 0.9 (0.6 to 1.4) for hypoplastic left ventricle, 0.9 (0.6 to 1.2) for transposition of the great arteries, and 1.0 (0.8 to 1.2) for conotruncal defects. Furthermore, no dose-effect pattern was identified. The findings of this study indicate that aspirin use during the first trimester of pregnancy does not increase the risk of congenital heart defects in relation to that of other structural malformations.

Pulmonary stenosis with ventricular septal defect, common aorticopulmonary trunk, and dextroposition of the aorta: morphologic and qualitative physiologic effects in caffeine-treated chick embryos.

Effects of caffeine administration to Hamburger-Hamilton stage 19 chick embryos (3 days of incubation) were investigated. A morphologic study of the effect of caffeine on cardiogenesis showed that caffeine produced total cardiac malformations in the chick in a dose-related fashion. A maximum frequency of 70.6% was observed with 4.7 mg caffeine. Major malformations included common aorticopulmonary trunk and dextroposition of the aorta accompanied by ventricular septal defect with/without pulmonary stenosis. Qualitative analysis of cinegraphs following exposure of embryos to a single teratogenic dose of caffeine (3.5 mg/egg) produced marked alterations in cardiac function when compared with chick Ringer's controls. Within 3 minutes after exposure to caffeine, dilation of the common ventricle and weak ventricular contractility were observed and persisted for 1 hour. Dose-response data and microcinematographic observations suggest that caffeine induced cardiac anomalies by a direct toxic effect on the embryo rather than by altering cardiac cell function. Our data also suggest that pathophysiologic changes in cardiac function may play an important role in the pathogenesis of caffeine-induced cardiac anomalies in the chick embryo.

Are female sex hormones teratogenic?

An analysis of available epidemiologic data leads the present reviewers to conclude that the use of exogenous hormones during human pregnancy has not been proved to cause developmental abnormality in nongenital organs and tissues. This conclusion is further supported by the animal laboratory data. The preponderance of evidence at this writing indicates a lack of causal association between hormonal use during pregnancy and nongenital malformation of the offspring. The quality of the epidemiologic data does not, at this time, permit a definitive conclusion that sex hormones during pregnancy may not, under as yet to be defined conditions, have some adverse effect on human prenatal development. If there are increased risks of nongenital malformations associated with the administration of certain sex steroids, the risks are very small, may not be causal, and are substantially below the spontaneous risk of malformations. In spite of the present degree of uncertainty, the clinical, epidemiologic, and laboratory data do permit the formulation of a rational approach to handling problems related to sex steroid usage and exposure in pregnant women.

PIP: This paper presents a comprehensive review of the literature on the teratogenicity of sex steroids, use of which during human pregnancy has been associated with developmental abnormalities in nontarget organs and tissues. A number of case-control and retrospective epidemiological studies published since 1967 suggest that there is a positive association between exposure to exogenous sex hormones during pregnancy and the birth of malformed infants. There have been more studies which negate, rather than demonstrate, the association between the exogenous use and nongenital malformations. These studies did not show any consistent type, pattern, or range of defects associated with exposure to exogenous use of female hormones during pregnancy. In addition, none of the claimed positive associations were able to relate increased risk of malformation to a particular type of hormone, although the hormones used included 3 pharmacologically different classes (estrogenic, progestational, androgenic). The various hormones used in the studies claiming positive associations were of widely varying potencies administered singly or collectively, over a broad range of dosage. Other epidemiologic and investigative sources of data strongly suggest at this time that use of exogenous hormones during human pregnancy has not been positively established to cause developmental abnormality in nongenital organs and tissues, and that the risks, if any, are very small, may not be causal, and are substantially below the spontaneous risk of malformation. Nevertheless, there has been unanimous agreement that sex steroid administration is not appropriate for diagnosing pregnancy, as there are better methods available for this purpose. Inadvertent exposure to sex steroids during pregnancy does not warrant pregnancy termination, but indiscriminate exposure to sex steroids or any drugs during pregnancy should be avoided. The historical aspect of the research work on the effects of sex hormones on the outcome of mammalian pregnancy is discussed, as are developmental defects (central nervous system defects, congenital heart defects, limb reduction malformation, and general malformation) in nontarget organs.

Transposition of the great vessels in an infant exposed to massive doses of oral contraceptives.

PIP: Drawing from evidence of complete dextro-transposition of the great vessels in approximately 2.0% of newborn infants with congenital heart disease, the authors suggest that this transposition may be associated with antenatal exposure to female sex hormones in the form of massive doses of oral contraceptives taken to induce abortion. Although causes of transpositions of the great vessels may be associated with single mutant gene defects or chromosomal aberrations, the study of familial aggregates, twin concordance, and animal models suggests that the majority of causes of congenital heart disease are a result of inherited genetic susceptibility to environmental events. Through previous intensive studies of pregnancies which have been inconclusive as well as data derived from the Collaborative Perinatal Project in which 50,282 mother-child pairs were tested, the increased relative risk of cardiovascular defects with female sex hormones was found to be 2.1 with a predominance of truncoconal anomalies. Since the important variables in the development of congenital malformation are: 1) the gestational age at the time of exposure, 2) the susceptibility of the individual to a given teratogen, and 3) the dose and duration of exposure to the teratogenic influence, the case study given in the article strengthens the hypothesis that truncoconal defects are associated with antenatal exposure to sex hormones.^ieng