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.

Use of oral fluconazole during pregnancy and the risk of birth defects.

BACKGROUND: Case reports suggest that long-term, high-dose fluconazole treatment for severe fungal infections during pregnancy causes a pattern of birth defects. It is unclear whether commonly used lower doses increase the risk of specific birth defects. METHODS: In a registry-based cohort of liveborn infants in Denmark, we evaluated first-trimester oral fluconazole exposure and the risk of birth defects overall and of birth defects previously linked to azole antifungal agents. RESULTS: The majority of fluconazole-exposed pregnancies were in women who received common therapeutic doses of 150 mg (56% of pregnancies) or 300 mg (31%). Oral fluconazole exposure was not associated with an increased risk of birth defects overall (210 birth defects among 7352 fluconazole-exposed pregnancies [prevalence, 2.86%] and 25,159 birth defects among 968,236 unexposed pregnancies [prevalence, 2.60%]; adjusted prevalence odds ratio, 1.06; 95% confidence interval [CI], 0.92 to 1.21). In addition, oral fluconazole exposure was not associated with a significantly increased risk of 14 of 15 types of birth defects previously linked to azole antifungal agents: craniosynostosis, other craniofacial defects, middle-ear defects, cleft palate, cleft lip, limb defects, limb-reduction defects, polydactyly, syndactyly, diaphragmatic hernia, heart defects overall, pulmonary-artery hypoplasia, ventricular septal defects, and hypoplastic left heart. A significantly increased risk of tetralogy of Fallot was observed (7 cases in fluconazole-exposed pregnancies [prevalence, 0.10%] as compared with 287 cases in unexposed pregnancies [prevalence, 0.03%]; adjusted prevalence odds ratio, 3.16; 95% CI, 1.49 to 6.71). CONCLUSIONS: Oral fluconazole was not associated with a significantly increased risk of birth defects overall or of 14 of the 15 specific birth defects of previous concern. Fluconazole exposure may confer an increased risk of tetralogy of Fallot. (Funded by the Danish Medical Research Council.).

Importance of timing of gestational exposure to methotrexate for its teratogenic effects when used in setting of misdiagnosis of ectopic pregnancy.

OBJECTIVE: To report a case of embryopathy due to misadministration of methotrexate in the setting of suspected ectopic pregnancy that resulted in a different pattern of malformations than is typically seen with methotrexate. DESIGN: Case report. SETTING: Community hospital. PATIENT(S): A 30-year-old primigravida women exposed to methotrexate (50 mg/m(2)) at 5 6/7 weeks' gestation. INTERVENTION(S): The patient underwent amniocentesis because of abnormal results at the first-trimester genetic screening (low levels of pregnancy associated plasma protein A and hCG) and fetal echocardiogram because of single umbilical artery. MAIN OUTCOME MEASURE(S): Fetal anomalies. RESULT(S): The fetus was found to have a single umbilical artery, tetralogy of Fallot, and a "horseshoe lung," despite administration of high doses of folic acid. The pregnancy ultimately ended with fetal demise at 30 weeks. CONCLUSION(S): As medical management of ectopic pregnancy becomes more common, practitioners should be cautious about the potential teratogenic effects in unrecognized intrauterine pregnancies and be able to diagnose the myriad defects, including cardiac anomalies, that could result from such exposure.

Tibial hemimelia and tetralogy of Fallot associated with first trimester exposure to amantadine.

Although amantadine hydrochloride has been extensively used for the prevention of influenza A2, few data exist regarding its safety in pregnancy. We report the outcome of a pregnancy during which the mother was treated with amantadine in the first trimester. The infant, born at 29 weeks gestation, has tetralogy of Fallot and tibial hemimelia. Follow-up of the four prospective cases known to date to the Motherisk Program in Toronto did not identify any abnormalities.

Hormonal versus genetic factors in limb and heart anomalies.

Three men, aged 18, 21 and 27 years, underwent surgery for atrial septal defect of the ostium secundum. All had bilateral absence of the forearm and thumb, with the rest of the hand directly attached to the upper arm. The patients had been exposed to synthetic progestogens during early intrauterine development. The oldest patient is described, together with a 6-year-old boy with limb reduction and Fallot's tetralogy who was exposed to the contraceptive pill during the first 2 months of gestation. During surgery he was found to have atrial septal defect of the ostium secundum. The most plausible diagnosis in such cases is the Holt-Oram syndrome, but the teratogenic effect of the synthetic hormones may be an important aetiological factor. Both hypotheses are discussed.

Tetralogy of Fallot, truncus arteriosus, abnormal myocardial architecture and anomalies of the aortic arch system induced by bis-diamine in rat fetuses.

OBJECTIVES: The aim of this study was to analyze the relation between anomalies of the heart and aortic arch arteries in near-term rat fetuses exposed to the chemical bis-diamine. BACKGROUND: Bis-diamine is known to induce cardiovascular anomalies. METHODS: Bis-diamine was given orally to normal pregnant rats, and the 65 fetuses were examined under a dissecting microscope after formalin fixation. RESULTS: There were 26 rat fetuses (40%) with a ventricular septal defect in the perimembranous portion, of which 14 (22%) had tetralogy of Fallot, 4 (6%) had truncus arteriosus and 8 (12%) had a relatively small defect with no other major anomalies. In 44 fetuses (68%) the middle latitudinal muscle bundle of the ventricular septum was continuous with the right ventricular free wall. There were, isolated or in association, a double- or right aortic arch in 6 fetuses (9%), aberrant subclavian arteries in 9 (14%), right ductus arteriosus in 12 (18%) and agenetic ductus in 4 (6%). The cross-sectional area of the ductus, as corrected by that of the aortic isthmus, was abnormally small in 47 rats (72%). The rat fetuses with a septal defect or abnormal myocardial architecture, or both, usually had a small ductus; it was very small or absent in those fetuses with tetralogy of Fallot. Of the four fetuses with truncus arteriosus, two had a vestigial vasculature on the truncus root and three had a rudimentary infundibulum. CONCLUSIONS: The cardinal defect may be the anomalous and reduced development of the sixth arch arteries, which by imposing pressure overload on the fetal right ventricle, may have led to either or both the persistence of ventricular septal defect as a vent or the formation of myocardial architecture favorable for the generation of pressure in the right ventricle.

[Extracardiac malformations in tetralogy of Fallot]. / Malformations extracardiaques dans la tétralogie de Fallot.

The purpose of our study was to determine the incidence and type of malformations associated with tetralogy of Fallot (TF). Among 133 patients followed up for 12 years, 30 who had either complete TF (n = 26) or pulmonary atresia and interventricular septal defect (n = 4) presented with another, extracardiac malformation. These malformations were part of a malformative syndrome in 21/30 patients, including 4 trisomies 21, 6 embryofoetopathies unquestionably (antiepileptics n = 2, alcohol n = 1) or possibly (hormonal treatment n = 1) of environmental origin, 6 branchial arch pathologies and 5 miscellaneous syndromes. The extracardiac malformation was isolated in the remaining 9 patients, including 5 cases of skeletal anomaly and one case each of omphalocele and microcephaly. Altogether, in these 30 patients skeletal and neurosensory anomalies were largely predominant. Skeletal anomalies involved the vertebral column in 8 cases (cervical 3, thoracic 4, lumbar 1) and the limbs in 5 cases (2 of which were phocomelias). The 4 patients with pulmonary atresia and interventricular septal defect also presented with an early embryopathy: Shprinzen's velocardiofacial syndrome (n = 2), DiGeorge syndrome (n = 1) and situs inversus (n = 1). We compared TF with other congenital heart diseases in our population and found that the incidence of associated malformations was about average. The various associations are discussed. In genetic syndromes, trisomy 21 predominates and TF is less frequent than atrioventricular canal. In syndromes of environmental origin, the role of antiepileptic drugs (chiefly phenytoin and trimethadione) is well-known, alcohol is less often responsible and the TF-phocomelia association is suggestive of progesterone. In branchial arch syndromes, TF is the usual cardiopathy.(ABSTRACT TRUNCATED AT 250 WORDS)

[Tetralogy of Fallot following coumarin administration in early pregnancy--an embryopathy?]. / Fallotsche Tetralogie nach Cumarineinnahme in der Frühschwangerschaft--eine Embryopathie?

A case report of a 35-year old woman is presented who continued a coumarin therapy unconscious of an early pregnancy up to day 61. At term she delivered a baby with tetralogy of Fallot, up to now not mentioned in the symptom complex of malformations due to a coumarin therapy. In the case presented the typical symptoms of a warfarin embryopathy including a chondrodysplasia punctata and other morphological changes were lacking. Although some cases of cardiac malformations have been reported in literature following coumarin therapy in early pregnancy, a causal connection could not be confirmed.