Intraamniotic digoxin administration versus intracardiac or funic potassium chloride administration to induce foetal demise before termination of pregnancy: a prospective study.

Different foeticide techniques and pharmacological agents have been used to achieve foetal asystole. This study aimed to compare the success of intraamniotic digoxin, intracardiac potassium chloride (KCl), and funic KCl in achieving foetal asystole and discuss procedural difficulties for physicians and clinical outcomes. This prospective observational study included 124 patients who received foeticide at 22-31 weeks of gestation. All procedures were performed transabdominally, and 1 mg of intraamniotic digoxin, funic KCl, or intracardiac KCl was administered. Procedure times, procedural difficulty scores, patient pain scores, decrease in haematocrit levels, induction and hospitalisation times, and the presence of chorioamnionitis were recorded. The foeticide success rates were 93.0, 95.1, and 97.5% for intraamniotic digoxin, intracardiac KCl, and funic KCl, respectively. Intraamniotic digoxin was associated with shorter procedure times, lower procedural difficulty scores, and lower patient pain scores (p < 0.001). Decreases in haematocrit, induction times, and chorioamnionitis were similar in all three procedures. Success rates and clinical results were similar for all three procedures. Foeticide with intra-amniotic digoxin has a high success rate, the procedure is easier to perform, and patients experience less procedural pain.IMPACT STATEMENTWhat is already known on this subject? Different foeticide techniques and pharmacological agents have been used to achieve foetal asystole. Pharmacological agents used in the foeticide procedure can be injected as intracardiac, funic, intrafetal, or intraamniotic, and the most commonly used are potassium chloride (KCl), digoxin, and lidocaine.What do the results of this study add? The success rates and clinical outcomes in achieving foetal asystole are similar for intracardiac KCl, funic KCl, and intra-amniotic digoxin procedures. Foeticide with intra-amniotic digoxin is less difficult to perform, and patients experience less pain associated with the procedure. All three techniques appear to be safe and have similar short-term obstetric outcomes.What are the implications of these findings for clinical practice and/or further research? Physicians may prefer foeticide with intra-amniotic digoxin as the procedure is technically simpler and has similar success rates to intracardiac or funic KCl administration. A prospective randomised study could better compare the advantages and limitations of the foeticide techniques.

Neutralizing Monoclonal Antibodies for Coronavirus Disease 2019 (COVID-19) in Pregnancy: A Case Series.

OBJECTIVE: To describe outcomes associated with monoclonal antibody use in pregnant persons with mild-to-moderate coronavirus disease 2019 (COVID-19). METHODS: We present a retrospective case series of pregnant patients who received anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibody infusions at a single center from April 1, 2021, through October 16, 2021. Pregnant patients who had a positive SARS-CoV-2 polymerase chain reaction (PCR) test result and mild-to-moderate COVID-19 symptoms were eligible for monoclonal antibody infusion. Exclusion criteria for administration included need for supplemental oxygen, hospitalization due to COVID-19, and positive SARS-CoV-2 PCR test result more than 7 days before screening. All patients received either bamlanivimab plus etesevimab or casirivimab plus imdevimab based on availability and dosing instructions of the product and emerging resistance patterns in the community. RESULTS: During the study period, monoclonal antibody infusions were administered to 450 individuals at our institution, of whom 15 were pregnant. Of the 15 pregnant persons receiving monoclonal antibody, six (40%) had full-vaccination status at the time of infusion. Two individuals (13%, CI 0-31%) experienced systemic reactions during the infusion, both resulting in temporary changes in the fetal heart rate tracing that recovered with maternal and intrauterine resuscitative efforts. One patient delivered after infusion for worsening maternal and fetal status; the remainder of the patients did not require admission for COVID-19. CONCLUSION: In this case series, pregnant persons who received anti-SARS-CoV-2 monoclonal antibody infusions had generally favorable outcomes.

Sodium dichloroacetate stimulates cardiac mitochondrial metabolism and improves cardiac conduction in the ovine fetus during labor.

Previous studies in our laboratory have suggested that the increase in stillbirth in pregnancies complicated by chronic maternal stress or hypercortisolemia is associated with cardiac dysfunction in late stages of labor and delivery. Transcriptomics analysis of the overly represented differentially expressed genes in the fetal heart of hypercortisolemic ewes indicated involvement of mitochondrial function. Sodium dichloroacetate (DCA) has been used to improve mitochondrial function in several disease states. We hypothesized that administration of DCA to laboring ewes would improve both cardiac mitochondrial activity and cardiac function in their fetuses. Four groups of ewes and their fetuses were studied: control, cortisol-infused (1 g/kg/day from 115 to term; CORT), DCA-treated (over 24 h), and DCA + CORT-treated; oxytocin was delivered starting 48 h before the DCA treatment. DCA significantly decreased cardiac lactate, alanine, and glucose/glucose-6-phosphate and increased acetylcarnitine/isobutyryl-carnitine. DCA increased mitochondrial activity, increasing oxidative phosphorylation (PCI, PCI + II) per tissue weight or per unit of citrate synthase. DCA also decreased the duration of the QRS, attenuating the prolongation of the QRS observed in CORT fetuses. The effect to reduce QRS duration with DCA treatment correlated with increased glycerophosphocholine and serine and decreased phosphorylcholine after DCA treatment. There were negative correlations of acetylcarnitine/isobutyryl-carnitine to both heart rate (HR) and mean arterial pressure (MAP). These results suggest that improvements in mitochondrial respiration with DCA produced changes in the cardiac lipid metabolism that favor improved conduction in the heart. DCA may therefore be an effective treatment of fetal cardiac metabolic disturbances in labor that can contribute to impairments of fetal cardiac conduction.

Phosphodiesterases Expression during Murine Cardiac Development.

3'-5' cyclic nucleotide phosphodiesterases (PDEs) are a large family of enzymes playing a fundamental role in the control of intracellular levels of cAMP and cGMP. Emerging evidence suggested an important role of phosphodiesterases in heart formation, but little is known about the expression of phosphodiesterases during cardiac development. In the present study, the pattern of expression and enzymatic activity of phosphodiesterases was investigated at different stages of heart formation. C57BL/6 mice were mated and embryos were collected from 14.5 to 18.5 days of development. Data obtained by qRT-PCR and Western blot analysis showed that seven different isoforms are expressed during heart development, and PDE1C, PDE2A, PDE4D, PDE5A and PDE8A are modulated from E14.5 to E18.5. In heart homogenates, the total cAMP and cGMP hydrolytic activity is constant at the evaluated times, and PDE4 accounts for the majority of the cAMP hydrolyzing ability and PDE2A accounts for cGMP hydrolysis. This study showed that a subset of PDEs is expressed in developing mice heart and some of them are modulated to maintain constant nucleotide phosphodiesterase activity in embryonic and fetal heart.

Antenatal betamethasone redistributes central blood flows and preferentially augments right ventricular output and pump function in preterm fetal lambs.

The glucocorticosteroid betamethasone, which is routinely administered prior to anticipated preterm birth to enhance maturation of the lungs and the cardiovascular system, has diverse fetal regional blood flow effects ranging from increased pulmonary flow to decreased cerebral flow. The aim of this study was to test the hypothesis that these diverse effects reflect alterations in major central flow patterns that are associated with complementary shifts in left ventricular (LV) and right ventricular (RV) pumping performance. Studies were performed in anesthetized preterm fetal lambs (gestation = 127 ± 1 days, term = 147 days) with (n = 14) or without (n = 12) preceding betamethasone treatment via maternal intramuscular injection. High-fidelity central arterial blood pressure and flow signals were obtained to calculate LV and RV outputs and total hydraulic power. Betamethasone therapy was accompanied by 1) increased RV, but not LV, output; 2) a greater RV than LV increase in total power; 3) a redistribution of LV output away from the fetal upper body region and toward the lower body and placenta; 4) a greater proportion of RV output passing to the lungs, and a lesser proportion to the lower body and placenta; and 5) a change in the relative contribution of venous streams to ventricular filling, with the LV having increased pulmonary venous and decreased foramen ovale components, and the RV having lesser superior vena caval and greater inferior vena caval portions. Taken together, these findings suggest that antenatal betamethasone produces a widespread redistribution of central arterial and venous flows in the fetus, accompanied by a preferential rise in RV pumping performance.

Agrin Yes-associated Protein Promotes the Proliferation of Epicardial Cells.

ABSTRACT: Embryonic epicardial cells make an important contribution to cardiac development. However, their proliferation mechanism is still unclear. Epicardial cells from E12.5 fetal hearts were used in our study. Agrin was used to treat these cells. The expression of Aurora B, Ki67, and pH3 was measured by quantitative reverse transcription-polymerase chain reaction and immunofluorescence. The proportion of cells in G1/S/G2 phase was determined by flow cytometry. The results showed that agrin significantly increased the expression of ki67, pH3, and Aurora B in epicardial cells. Flow cytometry results showed that agrin significantly increased the proportion of epicardial cells in S phase. However, blocking yes-associated protein significantly downregulated the levels of ki67, pH3, and Aurora B and the proportion of epicardial cells in S phase. Thus, our results suggest that agrin may promote the proliferation of epicardial cells by regulating the yes-associated protein activity. This may be useful in exploring heart development mechanisms and preventing congenital heart disease.

Effects of antenatal dexamethasone and hyperglycemia on cardiovascular adaptation to asphyxia in preterm fetal sheep.

Antenatal glucocorticoids improve outcomes among premature infants but are associated with hyperglycemia, which can exacerbate hypoxic-ischemic injury. It is still unclear how antenatal glucocorticoids or hyperglycemia modulate fetal cardiovascular adaptations to severe asphyxia. In this study, preterm fetal sheep received either saline or 12 mg im maternal dexamethasone, followed 4 h later by complete umbilical cord occlusion (UCO) for 25 min. An additional cohort of fetuses received titrated glucose infusions followed 4 h later by UCO to control for the possibility that hyperglycemia contributed to the cardiovascular effects of dexamethasone. Fetuses were studied for 7 days after UCO. Maternal dexamethasone was associated with fetal hyperglycemia (P < 0.001), increased arterial pressure (P < 0.001), and reduced femoral (P < 0.005) and carotid (P < 0.05) vascular conductance before UCO. UCO was associated with bradycardia, femoral vasoconstriction, and transient hypertension. For the first 5 min of UCO, fetal blood pressure in the dexamethasone-asphyxia group was greater than saline-asphyxia (P < 0.001). However, the relative increase in arterial pressure was not different from saline-asphyxia. Fetal heart rate and femoral vascular conductance fell to similar nadirs in both saline and dexamethasone-asphyxia groups. Dexamethasone did not affect the progressive decline in femoral vascular tone or arterial pressure during continuing UCO. By contrast, there were no effects of glucose infusions on the response to UCO. In summary, maternal dexamethasone but not fetal hyperglycemia increased fetal arterial pressure before and for the first 5 min of prolonged UCO but did not augment the cardiovascular adaptations to acute asphyxia.

Electrocardiographic QT Intervals in Infants Exposed to Hydroxychloroquine Throughout Gestation.

BACKGROUND: Based on inhibition of viral replication and limited reports on clinical efficacy, hydroxychloroquine is being considered as prophylaxis and treatment of coronavirus disease-19 (COVID-19). Although hydroxychloroquine is generally considered safe during pregnancy based on studies in patients with systemic lupus erythematosus and other rheumatic conditions, there may still be reluctance to institute this antimalarial during pregnancy for the sole purpose of antiviral therapy. METHODS: To provide data regarding any potential fetal/neonatal cardiotoxicity, we leveraged a unique opportunity in which neonatal ECGs and hydroxychloroquine blood levels were available in a recently completed study evaluating the efficacy of hydroxychloroquine 400 mg daily to prevent the recurrence of congenital heart block associated with anti-SSA/Ro (anti-Sjögren's Syndrome A/Ro) antibodies. RESULTS: Forty-five ECGs were available for corrected QT interval (QTc) measurement, and levels of hydroxychloroquine were assessed during each trimester of pregnancy and in the cord blood, providing unambiguous assurance of drug exposure. Overall, there was no correlation between cord blood levels of hydroxychloroquine and the neonatal QTc (R=0.02, P=0.86) or the mean of hydroxychloroquine values obtained throughout each individual pregnancy and the QTc (R=0.04, P=0.80). In total 5 (11% [95% CI, 4%-24%]) neonates had prolongation of the QTc >2 SD above historical healthy controls (2 markedly and 3 marginally) but ECGs were otherwise normal. CONCLUSIONS: In aggregate, these data provide reassurances that the maternal use of hydroxychloroquine is associated with a low incidence of infant QTc prolongation. However, if included in clinical COVID-19 studies, early postnatal ECGs should be considered. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01379573.

Early L-T4 intervention improves fetal heart development in pregnant rats with subclinical hypothyroidism rats by activating BMP4/Smad4 signaling pathway.

BACKGROUND: It is unclear whether the offspring of subclinical hypothyroidism (SCH) pregnant rats still have abnormal cardiac development, and whether early intervention with L-T4 can improve the abnormality of these offspring. Therefore, the aim of this study was to investigate the effect of early L-T4 intervention on the heart development of offspring of SCH pregnant rats and its possible molecular mechanism. METHODS: Eighty female Wistar rats were randomly divided into Sham group (placebo control), SCH group, LT4-E10 group (L-T4 treatment started on the 10th day of gestation), and LT4-E13 group (L-T4 treatment started on the 13th day of gestation). Each group was further divided into E16 (16th day of gestation), E18 (18th day of gestation), P5 (5th day postnatal day), and P10 (10th day postnatal day) subgroups. The levels of serum TT4 and TSH, the ratio of heart weight to body weight of offspring rats, the expression of metabolic enzymes, and the histopathology of cardiomyocytes were determined. To elucidate the effects of L-T4 on cardiac development of offspring of SCH pregnant rats, the expression levels of GATA4, Nkx2-5 and proteins involved in BMP4/Smad4 signaling pathway were detected by immunohistochemistry, real time quantitative polymerase chain reaction and Western blotting to elucidate the molecular mechanism of L-T4 regulating the heart development of the offspring of SCH pregnant rats. RESULTS: Compared with Sham group, serum TSH was significantly increased in SCH pregnant rats. Moreover, early L-T4 intervention significantly reduced the levels of serum TSH. Compared with the offspring in the SCH group, early L-T4 intervention significantly increased the heart weight, heart weight to body weight ratio, the activities of succinate dehydrogenase (SDH), Na+/K+-ATPase and Ca2+-ATPase, but reduced myocardial cell shrinkage and nuclear staining, hyperemia/congestion and vacuolar degeneration. In addition, early L-T4 intervention not only significantly increased the mRNA and protein expression of Gata4 and Nkx2-5, but also increased the protein expression involved in BMP4/Smad4 signal pathway in myocardium of the offspring of SCH pregnant rats. CONCLUSIONS: Early L-T4 intervention can regulate the cardiac development of the offspring of SCH pregnant rats by activating BMP4/Smad4 signaling pathway and increasing the expression of Gata4 and Nkx2-5 proteins.

Melatonin regulates oxidative stress and apoptosis in fetal hearts of pinealectomised RUPP rats.

OBJECTIVE: This study aimed to investigate the effects of melatonin on cardiac oxidative stress and apoptosis in the fetal heart in RUPP rats. METHODS: The fetal heart samples were obtained from melatonin administrated RUPP rats. RESULTS: Our results indicate that preeclampsia exacerbated by melatonin deficiency triggers hypoxic conditions, both mis/un-folded protein response, oxidative stress-induced DNA damage and apoptosis. Melatonin treatment provided significant therapeutic effects on fetal hearts via regulating all these stress response at cellular and molecular levels. CONCLUSION: Melatonin may be considered as a potential molecule for development of preventive strategies to reduce the PE induced risk of cardiovascular diseases in offspring.

Effects of nifedipine on fetal cardiac function in preterm labor.

Objectives To evaluate the effects of nifedipine treatment on fetal hemodynamics and cardiac function during preterm labor. This prospective study assessed several quantitative parameters of fetal cardiac circulation and function, and found no significant changes at 48 h after nifedipine treatment. These findings suggest that tocolytic nifedipine may be safe for fetuses. It supports clinicians to use nifedipine treatment for tocolysis without any cardiac effect on the fetus. Methods A prospective cohort study was conducted at a tertiary hospital between January 2016 and October 2017. A total of 45 pregnant women who required nifedipine for preterm labor were included in this study. Fetal Doppler ultrasound was performed and fetal systolic and diastolic function was measured prior to, and 48 h after, the first nifedipine treatment. Conventional Doppler parameters were used to evaluate fetal heart function and hemodynamic changes. Tricuspid annular plane systolic excursion, mitral annular plane systolic excursion and the sphericity index were also evaluated to assess changes in fetal cardiac morphology. Results No significant changes in fetal Doppler parameters were observed following nifedipine tocolysis. There was no significant difference in the fetal cardiac function parameters of both ventricles before vs. after nifedipine treatment. Tricuspid annular plane systolic excursion, mitral annular plane systolic excursion, and sphericity index values were unchanged following nifedipine treatment. Conclusions Oral administration of nifedipine did not to alter fetal cardiac function or morphology. Fetal cardiac parameters and various Doppler indices were unchanged following nifedipine treatment. Maternal nifedipine treatment does not appear to have any significant effect on fetal cardiac function.

Modulation of Paraoxonase-1 and Apoptotic Gene Expression Involves in the Cardioprotective Role of Flaxseed Following Gestational Exposure to Diesel Exhaust Particles and/or Fenitrothion Insecticide.

The developmental exposure to a single chemical may elicit apoptosis in the different fetal organs, while the combined effects are restricted. We have examined the protective role of flaxseed (FS) against diesel exhaust particles (DEPs)- and/or fenitrothion (FNT)-induced fetal cardiac oxidative stress and apoptosis. A total of 48 timed pregnant rats were divided into eight groups (n = 6). The first group was saved as the control and the second fed on 20% FS diet. Animals in the third, fourth, and fifth groups were administered with DEPs (2.0 mg/kg), FNT (3.76 mg/kg), and their combination, respectively, while the sixth, seventh, and eighth groups were supplemented with 20% FS through intoxication with DEPs, FNT, and their combination, respectively. Our results revealed that DEPs and/or FNT significantly elevated the level of protein carbonyl and superoxide dismutase activity in the fetal cardiac tissues. However, the catalase activity and total thiol level were decreased; besides the histopathological alterations were remarked. Moreover, DEPs and/or FNT exhibited significant down-regulation in the anti-apoptotic (Bcl-2) and paraoxonase-1 gene expression, and up-regulation in the apoptotic (Bax and caspase-3) gene expression along with DNA fragmentation. Remarkably, FS supplementation significantly ameliorated the fetal cardiac oxidative injury, down-regulated the expression of the apoptotic genes, up-regulated the anti-apoptotic and paraoxonase-1 gene expression, reduced DNA fragmentation, and alleviated the myocardial cell architectures. These findings revealed that FS attenuates DEPs- and/or FNT-induced apoptotic cell death by repairing the disturbance in the anti-apoptotic/pro-apoptotic gene balance toward cell survival in the fetal myocardial cells.

Research into the intervention effect of folic acid on arsenic-induced heart abnormalities in fetal rats during the periconception period.

BACKGROUND: The incidence of CHD is the highest among birth defects and is increasing year to year. CHD seriously harms the health of infants and young children and presents a large economic burden to families and society. The pathogenesis of CHD and preventive measures are the focus of current research. Our research aimed to explore the intervention effect of folic acid on heart abnormalities resulting from sodium arsenic (NaAsO2) exposure during the periconception period. METHODS: Sixty 35-day-old female SD rats were randomly divided into 5 groups with 12 rats in each group. Group A was the control group. The rats were given distilled water and ordinary chow. The rats in group B were given distilled water containing 75 mg/L NaAsO2 and ordinary chow. The rats in groups C, D, and E were given distilled water containing 75 mg/L NaAsO2 and chow containing 0.53 mg/kg, 5.3 mg/kg, and 10.6 mg/kg folic acid, respectively. The general condition of the embryos and the histopathology of the embryonic hearts were examined. The acetylation levels of histone H3K9 in heart tissues and the expression levels of Mef2C (which is related to heart development) were observed. RESULTS: The embryo weight and placental weight of groups B-E were significantly lower than those of group A (P < 0.05). The heart malformation rate of the fetal rats in groups B-E was significantly higher than that of the fetal rats in group A (P < 0.05). We found that the level of H3K9 acetylation in fetal rat cardiomyocytes in groups B-E was significantly higher than that in group A (P < 0.05) and that the level of H3K9 acetylation in groups C-E was lower than that in group B (P < 0.05). The mRNA level of Mef2C in fetal rat cardiomyocytes in group B-E was significantly higher than that in group A (P < 0.05), and the mRNA level of Mef2C in groups C-E was significantly lower than that in group B (P < 0.05). CONCLUSION: Supplementation with folic acid during the periconception period can interfere with the toxic effects of arsenic on the heart. The mechanism may be that lowering the acetylation levels of histone H3K9 in heart tissues leads to decreased expression levels of Mef2C, which may play a protective role in heart development in fetal rats.

Fetal ovine skeletal and cardiac muscle transcriptomics are differentially altered by increased maternal cortisol during gestation.

We have previously found that in utero exposure to excess maternal cortisol (1 mg/kg/day) in late gestation increases the incidence of stillbirth during labor and produces fetal bradycardia at birth. In the interventricular septum, mitochondrial DNA (mt-DNA) was decreased, and transcriptomics and metabolomics were consistent with altered mitochondrial metabolism. The present study uses transcriptomics to model effects of increased maternal cortisol on fetal biceps femoris. Transcriptomic modeling revealed that pathways related to mitochondrial metabolism were downregulated, whereas pathways for regulation of reactive oxygen species and activation of the apoptotic cascade were upregulated. Mt-DNA and the protein levels of cytochrome C were significantly decreased in the biceps femoris. RT-PCR validation of the pathways confirmed a significant decrease in SLC2A4 mRNA levels and a significant increase in PDK4, TXNIP, ANGPTL4 mRNA levels, suggesting that insulin sensitivity of the biceps femoris muscle may be reduced in cortisol offspring. We also tested for changes in gene expression in diaphragm by rt-PCR. PDK4, TXNIP, and ANGPTL4 mRNA were also increased in the diaphragm, but SLC2A4, cytochrome C protein, and mt-DNA were unchanged. Comparison of the change in gene expression in biceps femoris to that in cardiac interventricular septum and left ventricle showed few common genes and little overlap in specific metabolic or signaling pathways, despite reduction in mt-DNA in both heart and biceps femoris. Our results suggest that glucocorticoid exposure alters expression of nuclear genes important to mitochondrial activity and oxidative stress in both cardiac and skeletal muscle tissues, but that these effects are tissue-specific.

Systematic evaluation of mechanistic data in assessing in utero exposures to trichloroethylene and development of congenital heart defects.

The hypothesis that in utero exposures to low levels of trichloroethylene (TCE) may increase the risk of congenital heart defects (CHDs) in offspring remains a subject of substantial controversy within the scientific community due primarily to the reliance on an inconsistent and unreproducible experimental study in rats. To build on previous assessments that have primarily focused on epidemiological and experimental animal studies in developing conclusions, the objective of the current study is to conduct a systematic evaluation of mechanistic data related to in utero exposures to TCE and the development of CHDs. The evidence base was heterogeneous; 79 mechanistic datasets were identified, characterizing endpoints which ranged from molecular to organismal responses in seven species, involving both in vivo and in vitro study designs in mammalian and non-mammalian models. Of these, 24 datasets were considered reliable following critical appraisal using a study quality tool that employs metrics specific to the study type. Subsequent synthesis and integration demonstrated that the available mechanistic data: 1) did not support the potential for CHD hazard in humans, 2) did not support the biological plausibility of a response in humans based on organization via a putative adverse outcome pathway for valvulo-septal cardiac defects, and 3) were not suitable for serving as candidate studies in risk assessment. Findings supportive of an association were generally limited to in ovo chicken studies, in which TCE was administered in high concentration solutions via direct injection. Results of these in ovo studies were difficult to interpret for human health risk assessment given the lack of generalizability of the study models (including dose relevance, species-specific biological differences, variations in the construct of the study design, etc.). When the mechanistic data are integrated with findings from previous evaluations of human and animal evidence streams, the totality of evidence does not support CHDs as a critical effect in TCE human health risk assessment.

Drug exposure during pregnancy and fetal cardiac function - a systematic review.

Background The aim of this systematic review was to describe the effects of drug exposure during pregnancy on fetal cardiac function. Methods We searched MEDLINE, Embase, Cochrane and SCOPUS for studies assessing fetal cardiac function in drug-exposed human pregnancies. Risk of bias was assessed by the Risk Of Bias In Non-randomized Studies of Interventions (ROBIN-I) tool. Results We included 32 studies on eight different drug groups. They included 51 outcome variables, which were all based on ultrasound techniques primarily assessing systolic function: pulsed wave Doppler, tissue Doppler imaging (TDI), and B- and M-mode. Overall, the risk of bias was moderate. ß2 agonists increased the systolic velocity in the ductus arteriosus and the fetal heart rate. ß-blockers caused unchanged or decreased systolic velocity of the pulmonary trunk. Corticosteroids increased the velocity in the ductus arteriosus. Furthermore, in growth-restricted fetuses with an increased myocardial performance index (MPI') on the right side, corticosteroids normalized this variable. Nonsteroidal anti-inflammatory drugs (NSAIDs), but not acetylsalicylic acid, increased the flow velocities in the ductus arteriosus, decreased the shortening fraction and increased the end-diastolic ventricular diameters. Metformin and insulin normalized the diastolic strain and global longitudinal strain in diabetic pregnancies. Highly active antiretroviral therapy (HAART) exposure increased the E/A ratio on the right side, prolonged the isovolumic relaxation time (IRT) and ejection time, shortened the isovolumic contraction time (ICT), and decreased left myocardial systolic peak velocities. Chemotherapy did not cause detectable changes. Conclusion Six of the eight drug groups caused detectable changes in fetal cardiac function. However, the evidence was hampered by only a few studies for some drugs.

Low mortality in fetal supraventricular tachycardia: Outcomes in a 30-year single-institution experience.

OBJECTIVES: To describe a single institutional experience managing fetuses with supraventricular tachycardia (SVT) and to identify associations between patient characteristics and fetal and postnatal outcomes. BACKGROUND: Sustained fetal SVT is associated with significant morbidity and mortality if untreated, yet the optimal management strategy remains unclear. METHODS: Retrospective cohort study including fetuses diagnosed with sustained SVT (>50% of the diagnostic echocardiogram) between 1985 and 2018. Fetuses with congenital heart disease were excluded. RESULTS: Sustained SVT was diagnosed in 65 fetuses at a median gestational age of 30 weeks (range, 14-37). Atrioventricular re-entrant tachycardia and atrial flutter were the most common diagnoses, seen in 41 and 16 cases, respectively. Moderate/severe ventricular dysfunction was present in 20 fetuses, and hydrops fetalis was present in 13. Of the 57 fetuses initiated on transplacental drug therapy, 47 received digoxin first-line, yet 39 of 57 (68%) required advanced therapy with sotalol, flecainide, or amiodarone. Rate or rhythm control was achieved in 47 of 57 treated fetuses. There were no cases of intrauterine fetal demise. Later gestational age at fetal diagnosis (odds ratio [OR], 1.1, 95% confidence interval [CI], 1.01-1.2, P = .02) and moderate/severe fetal ventricular dysfunction (OR, 6.1, 95% CI, 1.7-21.6, P = .005) were associated with postnatal SVT. Two postnatal deaths occurred. CONCLUSIONS: Fetuses with structurally normal hearts and sustained SVT can be effectively managed with transplacental drug therapy with minimal risk of intrauterine fetal demise. Treatment requires multiple antiarrhythmic agents in over half of cases. Later gestational age at fetal diagnosis and the presence of depressed fetal ventricular function, but not hydrops, predict postnatal arrhythmia burden.

Maternal administration of tadalafil improves fetal ventricular systolic function in a Hey2 knockout mouse model of fetal heart failure.

BACKGROUND: There is no established transplacental treatment for heart failure (HF) in utero, and no animal models or experimental systems of fetal HF have been established. This study aimed to investigate the effect of maternal tadalafil administration on fetal cardiovascular function and uteroplacental circulation in a murine model of fetal HF. METHODS AND RESULTS: We first used an ultra-high-frequency ultrasound imaging system in utero and demonstrated that Hey2-/- embryos had worsening right ventricular hypoplasia and marked left ventricular (LV) dilatation as gestation progressed. In both ventricles, fractional shortening (FS) and the E/A ratio were significantly lower in Hey2-/- embryos than in wild-type embryos, indicating that the embryos can be used as a murine model of fetal HF. Subsequently, we evaluated the effect of tadalafil treatment (0.04 or 0.08 mg/ml; T0.04 or T0.08 groups, respectively) on fetoplacental circulation in Hey2-/- embryos. LV FS was significantly higher in the T0.04 group than in control (P < 0.01), whereas LV dilation, mitral E/A ratio, and umbilical artery resistance index were not significantly different among all groups. The thinness of the LV compacted layer did not differ between the T0.04 and vehicle-treated Hey2-/- embryos. CONCLUSIONS: A phenotype comprising marked dilatation and reduced FS of the left ventricles was identified in Hey2-/- embryos, suggesting these embryos as a murine model of fetal HF. In addition, maternal administration of tadalafil improved LV systolic function without altering LV morphological abnormalities in Hey2-/- embryos. Our findings suggest that tadalafil is a potential agent to treat impaired fetal ventricular systolic function.

Characterizing the effects of in utero exposure to valproic acid on murine fetal heart development.

BACKGROUND: Recently, the use of the antiepileptic drug valproic acid (VPA) for the treatment of psychiatric conditions has been on the rise. However, studies have shown that in utero VPA exposure can affect embryonic development, including being associated with congenital heart defects. One proposed mechanism of VPA-initiated teratogenicity is the inhibition of histone deacetylase, which is involved in the regulation of transcription factors that regulate cardiogenesis. Myocyte enhancing factor 2C (Mef2c), a transcription factor involved in the development of cardiac structure and cardiomyocyte differentiation, has been shown to increase in response to in utero VPA exposure, associating with contractile dysfunction and myocardial disorganization. METHODS: To characterize the effects of VPA on murine heart development, pregnant CD-1 mice were dosed with 400 mg/kg of VPA on gestational day (GD) 9. Using high-resolution ultrasound, we examined the effects of VPA on cardiac contractile function on GD 14-18, with fetal hearts being harvested on GD 19 for histological analysis. Lastly, we conducted quantitative real-time polymerase chain reaction to measure the relative Mef2c gene expression in GD 16 murine hearts. RESULTS: We observed structural anomalies at GD 19 in the hearts of VPA-treated mice. Additionally, our results showed alterations in measures of cardiac contractility, with a decrease or increase in cardiac contractile ability in VPA-treated mice depending on the GD and measurement taken. CONCLUSIONS: These results further characterize the effects of VPA on heart development and suggest that alterations in Mef2c gene expression, at least on GD 16, do not mediate VPA-induced cardiotoxicity in CD-1 mice.

Magnetocardiographic identification of prolonged fetal corrected QT interval in women receiving treatment for opioid use disorder.

AIM: Pregnant women undergoing treatment for opioid use disorder (OUD) may be exposed to multiple QT prolonging agents. We used magnetocardiography to measure fetal QT intervals in mothers with OUD on buprenorphine therapy. METHODS: Fetal and maternal magnetocardiography was performed in pregnant women receiving buprenorphine-assisted treatment (Disorder group); these were matched by gestational age to pregnant women who were opiate naïve (Reference group). Corrected QT intervals were determined using Bazett's formula and compared between groups. RESULTS: A total of eight women in the Disorder group matched to eight in the Reference group. Seven of the mothers (88%) in the Disorder group were smokers; there were no smokers in the Reference group. The average fetal corrected QT was significantly longer (P = 0.022) in the Disorder group than that in the Reference group (505 milliseconds [ms] ± 68.6 [standard deviation] vs 383 ms ± 70.3 [standard deviation]). CONCLUSION: Novel data from this small sample demonstrate prolongation of fetal corrected QT in women with OUD participating in buprenorphine assisted therapy. Additional investigation from a larger sample is needed to clarify if fetal buprenorphine and/or tobacco exposure is associated with changes in fetal QT which would warrant further prenatal and postnatal testing.