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Objective: Fetoscopic closure of spina bifida using heated and humidified carbon dioxide gas (hhCO 2 ) has been associated with lower maternal morbidity compared with open closure. Fetal cardiovascular changes during these surgical interventions are poorly defined. Our objective was to compare fetal bradycardia (defined as fetal heart rate (FHR) < 110 bpm for 10 min) and changes in umbilical artery (UA) Doppler parameters during open vs fetoscopic closure., Methods: This was a prospective cohort study of 22 open and 46 fetoscopic consecutive in-utero closures conducted between 2019 and 2023. Both cohorts had similar preoperative counseling and clinical management. FHR and UA Doppler velocimetry were obtained systematically during preoperative assessment, every 5 min during the intraoperative period, and during the postoperative assessment. FHR, UA pulsatility index (PI) and UA end-diastolic flow (EDF) were segmented into hourly periods during surgery, and the lowest values were averaged for analysis. Umbilical vein maximum velocity was measured in the fetoscopic cohort. At each timepoint at which FHR was recorded, maternal heart rate and systolic and diastolic blood pressure were measured., Results: Fetal bradycardia occurred in 4/22 (18.2%) cases of open closure and 21/46 (45.7%) cases of fetoscopic closure (P = 0.03). FHR decreased gradually in both cohorts after administration of general anesthesia and decreased further during surgery. FHR was significantly lower during hour 2 of surgery in the fetoscopic-repair cohort compared with the open-repair cohort. The change in FHR from baseline in the final stage of fetal surgery was significantly more pronounced in the fetoscopic-repair cohort compared with the open-repair cohort (mean, -32.4 (95% CI, -35.7 to -29.1) bpm vs -23.5 (95% CI, -28.1 to -18.8) bpm; P = 0.002). Abnormal UA-EDF (defined as absent or reversed EDF) occurred in 3/22 (13.6%) cases in the open-repair cohort and 23/46 (50.0%) cases in the fetoscopic-repair cohort (P = 0.004). There were no differences in UA-EDF or UA-PI between closure techniques at the individual stages of assessment., Conclusions: We observed a decrease in FHR and abnormalities in UA Doppler parameters during both open and fetoscopic spina bifida closure. Fetal bradycardia was more prominent during fetoscopic closure following hhCO 2 insufflation, but FHR recovered after cessation of hhCO 2 . Changes in FHR and UA Doppler parameters during in-utero spina bifida closure were transient, no cases required emergency delivery and no fetoscopic closure was converted to open closure. These observations should inform algorithms for the perioperative management of fetal bradycardia associated with in-utero spina bifida closure. © 2024 International Society of Ultrasound in Obstetrics and Gynecology., (© 2024 International Society of Ultrasound in Obstetrics and Gynecology.)

Objectives: To evaluate the effect of transient fetal bradycardia and other heart rate changes during and after external cephalic version (ECV) on perinatal outcomes. To determine factors associated with a higher risk of occurrence of transient fetal bradycardia during and after ECV., Study Design: Prospective study in 286 women after the 36th week of gestation with a fetus in breech presentation who have undergone an ECV attempt. The study analyses the incidence of transient fetal bradycardia during and immediately after ECV, the time interval to complete adjustment of fetal bradycardia, the factors associated with the occurrence of transient fetal bradycardia, cardiotocography (CTG) changes after ECV and perinatal outcomes. All the data were statistically analyzed., Results: The ECV was successful in 51 % (146/286). Transient fetal bradycardia occurred during and after ECV in 81 cases (28.3 %). A successful version was a factor significantly associated with fetal bradycardia (54; 37.0 % versus 27; 19.3 %; p < 0.01). Clinically significant hypotension of the mother was accompanied by transient fetal bradycardia in 12 cases (4.2 %). After the successful ECV there was no significant difference in the percentage of vaginal deliveries between subgroups with and without transient fetal bradycardia (85.2 % versus 83.7 %; p = 1.00). Nor in occurrence of acute fetal distress during labor (18.5 % versus 15.6 %; p = 0.65). In cases of a successful ECV transient CTG changes after ECV had no effect on the incidence of acute fetal distress during labor (23.5 % versus 15.7 %; p = 0.49)., Conclusions: Transient fetal bradycardia and other heart rate changes during and immediately after ECV was not associated with a higher incidence of acute fetal distress during labor and did not affect perinatal outcomes. Higher occurrence of transient bradycardia after ECV was associated only with successful ECV. Transient hypotension of the mother as one of the causes of transient fetal bradycardia during ECV should be considered., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A prospective study was conducted for comparing the incidence of fetal bradycardia and level of fetal heart rate change following a second-trimester genetic amniocentesis with and without placental injury. A total of 257 and 495 participants in injured and non-injured groups were analysed. The incidence of fetal bradycardia following amniocentesis was not statistically different between the two groups (1.17%, [95% CI 0.24, 3.37] and 0.20%, [95% CI 0.005, 1.12]) in injured and non-injured placenta groups, respectively; p = 0.118). The mean change in baseline fetal heart rate before and after amniocentesis was also not significantly different between the two groups (p = 0.844). No fetal death or pregnancy loss occurred within 4 weeks after the procedure. All 4 bradycardia participants were normal and healthy and had an appropriate weight for their gestational age. We conclude that placental injury during a second-trimester genetic amniocentesis due to advanced maternal age poses only a low risk of fetal bradycardia, and there is no evidence of differences between subjects with injured and non-injured placenta in the changes in fetal heart rate.

Background: Embryo resorption is a major problem in human medicine, agricultural animal production and in conservation breeding programs. Underlying mechanisms have been investigated in the well characterised mouse model. However, post mortem studies are limited by the rapid disintegration of embryonic structures. A method to reliably identify embryo resorption in alive animals has not been established yet. In our study we aim to detect embryos undergoing resorption in vivo at the earliest possible stage by ultra-high frequency ultrasound., Methods: In a longitudinal study, we monitored 30 pregnancies of wild type C57BI/6 mice using ultra-high frequency ultrasound (30-70 MHz), so called ultrasound biomicroscopy (UBM). We compared the sonoembryology of mouse conceptuses under spontaneous resorption and neighbouring healthy conceptuses and correlated the live ultrasound data with the respective histology., Results: The process of embryo resorption comprised of four stages: first, the conceptus exhibited growth retardation, second, bradycardia and pericardial edema were observed, third, further development ceased and the embryo died, and finally embryo remnants were resorbed by maternal immune cells. In early gestation (day 7 and 8), growth retardation was characterized by a small embryonic cavity. The embryo and its membranes were ill defined or did not develop at all. The echodensity of the embryonic fluid increased and within one to two days, the embryo and its cavity disappeared and was transformed into echodense tissue surrounded by fluid filled caverns. In corresponding histologic preparations, fibrinoid material interspersed with maternal granulocytes and lacunae filled with maternal blood were observed. In later stages (day 9-11) resorption prone embryos were one day behind in their development compared to their normal siblings. The space between Reichert's membrane and inner yolk sac membrane was enlarged The growth retarded embryos exhibited bradycardia and ultimately cessation of heart beat. Corresponding histology showed apoptotic cells in the embryo while the placenta was still intact. In the subsequent resorption process first the embryo and then its membranes disappeared., Conclusions: Our results provide a temporal time course of embryo resorption. With this method, animals exhibiting embryo resorption can be targeted, enabling the investigation of underlying mechanisms before the onset of total embryo disintegration.

The Swedish Medical Product Agency (MPA) has listed erythromycin as a suggested human teratogen, causing cardiovascular malformations. It is further suggested that this may be a class effect of macrolide antibiotics. The proposed teratogenic mechanism is blockade of the human ether-á-go-go-related (hERG)/IKr current in the embryonic heart causing bradycardia and arrhythmia resulting in altered cardiac blood flow and/or embryonic hypoxia. To test this hypothesis, we examined the effect of three macrolide antibiotics on the function of the rat embryonic heart. Gestational day 13 rat embryos in vitro were exposed to erythromycin (25-500 μM), clarithromycin (25-500 μM), or azithromycin (100 μM to 1 mM) for 3 hr. The effect on the embryonic heart was monitored every hour. The results showed that erythromycin and clarithromycin caused a concentration-dependent bradycardia. Twenty-five micromolar was a no-effect concentration for erythromycin and was close to a no-effect concentration for clarithromycin. Azithromycin only caused significant bradycardia at 1 mM. Additional studies were performed with the embryos cultured at 40°C instead of 38°C, to mimic fever. The increased temperature increased the number of arrhythmias but did not worsen the drug-induced bradycardia. The results support the concept that erythromycin and clarithromycin can adversely affect the embryonic heart but only at concentrations well outside expected embryonic exposure in the human., (© 2014 Wiley Periodicals, Inc.)

During the organogenic period of development the cardiovascular system of the embryo fulfills several functions including delivery of oxygen and nutrients and a hemodynamic role necessary for cardiac morphogenesis, angiogenesis and hematopoiesis. It is expected that at each stage of embryonic development there is an ideal embryonic heart rate and contractility that maintains the optimal blood flow and pressure to fulfill these various functions. In vitro rat embryo culture studies have revealed that many therapeutic drugs (antiarrhythmics, antidepressants, antipsychotics and anticonvulsants), that may be taken during human pregnancy, cause a concentrationdependent slowing of the embryonic heart and irregular heart rate at higher concentrations. The concentrations causing bradycardia in vitro are often close to human therapeutic plasma concentrations and raise concern that these drugs can potentially cause embryonic death or malformations, and that current reproductive toxicity testing does not adequately examine possible effects of drugs on the embryo's cardiac function.

This study was undertaken to examine the effect on the rat embryonic heart of two experimental drugs (AZA and AZB) which are known to block the sodium channel Nav1.5, the hERG potassium channel and the l-type calcium channel. The sodium channel blockers bupivacaine, lidocaine, and the l-type calcium channel blocker nifedipine were used as reference substances. The experimental model was the gestational day (GD) 13 rat embryo cultured in vitro. In this model the embryonic heart activity can be directly observed, recorded and analyzed using computer assisted image analysis as it responds to the addition of test drugs. The effect on the heart was studied for a range of concentrations and for a duration up to 3h. The results showed that AZA and AZB caused a concentration-dependent bradycardia of the embryonic heart and at high concentrations heart block. These effects were reversible on washout. In terms of potency to cause bradycardia the compounds were ranked AZB>bupivacaine>AZA>lidocaine>nifedipine. Comparison with results from previous studies with more specific ion channel blockers suggests that the primary effect of AZA and AZB was sodium channel blockage. The study shows that the short-term rat whole embryo culture (WEC) is a suitable system to detect substances hazardous to the embryonic heart., (© 2013.)

Background: Dofetilide is an antiarrhythmic drug that blocks the cardiac repolarizing current IKr ((IKr, rapid component of the delayed rectifying potassium current). Previous studies have shown that (a) IKr is essential for normal cardiac function of the embryonic heart and (b) dofetilide is teratogenic in rodents. This study was undertaken to examine the mechanism by which dofetilide causes limb defects on gestational day 13 (GD 13) in the rat., Methods: Rats were treated with dofetilide (single oral dose, 5 mg/kg) on GD 13 and embryonic heart rates assessed by ultrasound (Vevo770, VisualSonics, Toronto, Ontario, Canada) 2 hr later. Fetuses were examined for malformations on GD 20. In a separate experiment, dofetilide treatment of GD 13 rats was followed 2, 4, 12, or 24 hr with iv dosing with the hypoxia marker, pimonidazole (60 mg/kg). Embryos were collected and heart rates were assessed in vitro and hypoxia in embryo limbs analyzed., Results: A teratogenic dose of dofetilide at a susceptible stage of development (GD 13) resulted in a period of bradycardia and arrhythmia of the embryonic heart and hypoxia in the developing limbs (GD 13) resulting in limb malformations (GD 20)., Conclusions: Drugs that induce periods of bradycardia and/or arrhythmia of the embryonic heart and cause the embryo to become hypoxic are potential human teratogens., (© 2013 Wiley Periodicals, Inc.)

The mortality and morbidity of fetal aortic stenosis (AS) depend on the degree of the hemodynamic effects of the stenosis, and left ventricular (LV) adaptation, development and function during fetal life. In the case of critical AS, the development of hydrops and death in utero are well recognized entities. A 23-week gestation fetus was diagnosed with critical severe AS, cardiomegaly, a dilated LV with very poor contractility, and mitral regurgitation. There was a reversal of flow in the aortic arch through the ductus arteriosis and a reversed a-wave in the ductus venosus on Doppler examination. The fetus had hydrops with ascites, and massive scalp, face and skin edema. Fetal amniocentesis was normal. Aortic valvuloplasty was performed under general anesthesia and echocardiographic guidance. Pericardial effusion was not observed after the procedure. However, LV function could not be ameliorated and continued to diminish. There was no cardiac activity in the fetus two hours after the intervention. Aortic valvuloplasty in utero for AS is technically feasible. Mortality is mainly associated with technical errors, LV function, and the degree of endofibroelastosis in the effected fetuses.

Metal-on-metal hip arthroplasty has been performed with increasing frequency throughout the world, particularly in younger and more active patients, including women of childbearing age. The potential toxicity of cobalt exposure on fetus is concerned since cobalt ions generated by metal-on-metal bearings can traverse the placenta and be detected in fetal blood and amniotic fluid. This study examined the effects of cobalt exposure on early embryonic development and the mechanisms underlying its toxicity. Zebrafish embryos were exposed to a range of cobalt concentrations (0-100 mg/L) between 1 and 144 h postfertilization. The survival and early development of embryos were not significantly affected by cobalt at concentrations <100 μg/L. However, embryos exposed to higher concentrations (>100 μg/L) displayed reduced survival rates and abnormal development, including delayed hatching, aberrant morphology, retarded growth, and bradycardia. Furthermore, this study examined oxidative stress and apoptosis in embryos exposed to cobalt at concentrations of 0-500 μg/L. Lipid peroxidation levels were increased in cobalt-treated embryos at concentrations of 100 and 500 μg/L. The mRNA levels of catalase, superoxide dismutase 2, p53, caspase-3, and caspase-9 genes were upregulated in a dose-dependent manner. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assays also revealed abnormal apoptotic signals in the brain, trunk, and tail when treated with 500 μg/L cobalt. These data suggest that oxidative stress and apoptosis are associated with cobalt toxicity in zebrafish embryos.

This study investigated the effects of a range of antidepressant drugs on the heart of gestation day 13 rat embryos in vitro. The general hypothesis was that the drugs would adversely affect the function of the embryonic heart since they all have some cardiac ion channel blocking activity in addition to their main pharmacological effect on neurotransmitters. The results showed that all the tested drugs caused bradycardia in a generally concentration-dependent manner. At higher concentrations most of the drugs caused some degree of heart block consistent with sodium channel blockade and some drugs also showed negative inotropy associated with blockade of the L-type calcium channel. One drug, trazodone, caused arrhythmia consistent with blockade of the hERG (human ether-a-go-go related gene) potassium channel. In general the effects on the embryonic rat heart were only seen at "free drug" concentrations much greater than those likely to occur in pregnant women taking antidepressant medication. The least margin of safety was seen with the tricyclic antidepressants and the serotonin antagonist and reuptake inhibitor trazodone., (© 2012 Wiley Periodicals, Inc.)

Objectives: To study fetal wellbeing and uteroplacental blood flow during strenuous treadmill running in the second trimester., Methods: Six pregnant Olympic-level athletes in endurance events aged 28-37 years and training 15-22 h per week before the pregnancy were tested once at 23-29 weeks of pregnancy. The women ran three to five submaximal workloads on a treadmill with approximately 60-90% of maximal oxygen consumption. The maternal-fetal circulation was assessed with Doppler ultrasound of the uterine and umbilical arteries before, during and after exercise., Results: Mean uterine artery volume blood flow was reduced to 60-80% after warming up and stayed at 40-75% of the initial value during exercise. Fetal heart rate (FHR) was within the normal range (110-160 bpm) as long as the woman exercised below 90% of maximal maternal heart rate (MHR). Fetal bradycardia and high umbilical artery pulsatility index (PI) occurred when the woman exercised more than 90% of maximal MHR and the mean uterine artery volume blood flow was less than 50% of the initial value. FHR and umbilical artery PI normalised quickly after stopping the exercise., Conclusions: Exercise at intensity above 90% of maximal MHR in pregnant elite athletes may compromise fetal wellbeing.

Petroleum-derived compounds, including polycyclic aromatic hydrocarbons (PAHs), commonly occur as complex mixtures in the environment. Recent studies using the zebrafish experimental model have shown that PAHs are toxic to the embryonic cardiovascular system, and that the severity and nature of this developmental cardiotoxicity varies by individual PAH. In the present study we characterize the toxicity of the relatively higher molecular weight 5-ring PAHs benzo[a]pyrene (BaP), benzo[e]pyrene (BeP), and benzo[k]fluoranthene (BkF). While all three compounds target the cardiovascular system, the underlying role of the ligand-activated aryl hydrocarbon receptor (AHR2) and the tissue-specific induction of the cytochrome p450 metabolic pathway (CYP1A) were distinct for each. BaP exposure (40μM) produced AHR2-dependent bradycardia, pericardial edema, and myocardial CYP1A immunofluorescence. By contrast, BkF exposure (4-40μM) caused more severe pericardial edema, looping defects, and erythrocyte regurgitation through the atrioventricular valve that were AHR2-independent (i.e., absent myocardial or endocardial CYP1A induction). Lastly, exposure to BeP (40μM) yielded a low level of CYP1A+ signal in the vascular endothelium of the head and trunk, without evident toxic effects on cardiac function or morphogenesis. Combined with earlier work on 3- and 4-ring PAHs, our findings provide a more complete picture of how individual PAHs may drive the cardiotoxicity of mixtures in which they predominate. This will improve toxic injury assessments and risk assessments for wild fish populations that spawn in habitats altered by overlapping petroleum-related human impacts such as oil spills, urban stormwater runoff, or sediments contaminated by legacy industrial activities., (Published by Elsevier Inc.)

The vertebrate heart is one of the first organs to form, and its early function and morphogenesis are crucial for continued embryonic development. Here we analyze the effects of loss of Heart adaptor protein 1 (Hadp1), which we show is required for normal function and morphogenesis of the embryonic zebrafish heart. Hadp1 is a pleckstrin homology (PH)-domain-containing protein whose expression is enriched in embryonic cardiomyocytes. Knockdown of hadp1 in zebrafish embryos reduced cardiac contractility and altered late myocyte differentiation. By using optical mapping and submaximal levels of hadp1 knockdown, we observed profound effects on Ca(2+) handling and on action potential duration in the absence of morphological defects, suggesting that Hadp1 plays a major role in the regulation of intracellular Ca(2+) handling in the heart. Hadp1 interacts with phosphatidylinositol 4-phosphate [PI4P; also known as PtdIns(4)P] derivatives via its PH domain, and its subcellular localization is dependent upon this motif. Pharmacological blockade of the synthesis of PI4P derivatives in vivo phenocopied the loss of hadp1 in zebrafish. Collectively, these results demonstrate that hadp1 is required for normal cardiac function and morphogenesis during embryogenesis, and suggest that hadp1 modulates Ca(2+) handling in the heart through its interaction with phosphatidylinositols.

Dextromethorphan is widely used in over-the-counter cough and cold medications. Its efficacy and safety for infants and young children remains to be clarified. The present study was designed to use zebrafish as a model to investigate the potential toxicity of dextromethorphan during embryonic and larval development. Three sets of zebrafish embryos/larvae were exposed to dextromethorphan at 24, 48 and 72 h post fertilization (hpf), respectively, during the embryonic/larval development. Compared with the 48 and 72 hpf exposure sets, the embryos/larvae in the 24 hpf exposure set showed much higher mortality rates which increased in a dose-dependent manner. Bradycardia and reduced blood flow were observed for the embryos/larvae treated with increasing concentrations of dextromethorphan. Morphological effects of dextromethorphan exposure, including yolk sac and cardiac edema, craniofacial malformation, lordosis, non-inflated swim bladder and missing gill, were also more frequent and severe among zebrafish embryos/larvae exposed to dextromethorphan at 24 hpf. Whether the more frequent and severe developmental toxicity of dextromethorphan observed among the embryos/larvae in the 24 hpf exposure set, as compared with the 48 and 72 hpf exposure sets, is due to the developmental expression of the phase I and phase II enzymes involved in the metabolism of dextromethorphan remains to be clarified. A reverse transcription-polymerase chain reaction analysis, nevertheless, revealed developmental stage-dependent expression of mRNAs encoding SULT3 ST1 and SULT3 ST3, two enzymes previously shown to be capable of sulfating dextrorphan, an active metabolite of dextromethorphan., (Copyright © 2010 John Wiley & Sons, Ltd.)

This study investigated the effects of a range of pharmaceutical drugs with ion channel-blocking activity on the heart of gestation day 13 rat embryos in vitro. The general hypothesis was that the blockade of the I(Kr)/hERG channel, that is highly important for the normal functioning of the embryonic rat heart, would cause bradycardia and arrhythmia. Concomitant blockade of other channels was expected to modify the effects of hERG blockade. Fourteen drugs with varying degrees of specificity and affinity toward potassium, sodium, and calcium channels were tested over a range of concentrations. The rat embryos were maintained for 2 hr in culture, 1 hr to acclimatize, and 1 hr to test the effect of the drug. All the drugs caused a concentration-dependent bradycardia except nifedipine, which primarily caused a negative inotropic effect eventually stopping the heart. A number of drugs induced arrhythmias and these appeared to be related to either sodium channel blockade, which resulted in a double atrial beat for each ventricular beat, or I(Kr)/hERG blockade, which caused irregular atrial and ventricular beats. However, it is difficult to make a precise prediction of the effect of a drug on the embryonic heart just by looking at the polypharmacological action on ion channels. The results indicate that the use of the tested drugs during pregnancy could potentially damage the embryo by causing periods of hypoxia. In general, the effects on the embryonic heart were only seen at concentrations greater than those likely to occur with normal therapeutic dosing., (© 2010 Wiley-Liss, Inc.)

In the present review we outline the state-of-the-art of neuraxial analgesia. As neuraxial analgesia remains the gold standar of analgesia during labor, we review the most recent literature on this topic. The neuraxial analgesia techniques, types of administration, drugs, adjuvants, and adverse effects are investigated from the references. Most authors would agree that central neuraxial analgesia is the best form to manage labor pain. When neuraxial analgesia is administered to the parturient in labor, different management choices must be made by the anesthetist: how will we initiate analgesia, how will analgesia be maintained, which local anesthetic will we use for neuraxial analgesia and which adjuvant drugs will we combine? The present manuscript tries to review the literature to answer these questions.

Left ventricular noncompaction (LVNC) is an uncommon disorder that has recently been recognized as a distinct cardiomyopathy. LVNC is thought to result from an arrest in the normal process of myocardial compaction. The association of Wolff-Parkinson-White with noncompaction of the left ventricle is well recognized. Sinus bradycardia has also been associated with LVNC, although less frequently than that of Wolff-Parkinson-White. We report an infant with LVNC, Wolff-Parkinson-White, and progressive sinus bradycardia who had a myocardial vascular abnormality in the region of the sinus node evident on autopsy. We propose that the progressive nature of the conduction system abnormality was as a result of abnormal angiogenesis.

Complete atrioventricular block (CAVB) is the most common cause of persistent fetal bradycardia. In the presence of a structurally normal heart, it develops primarily in anti-Ro and anti-La positive antibody pregnancies after 20 weeks of gestation. There is a significant risk of perinatal demise, particularly in association with fetal hydrops, poor ventricular function, and heart rates < 55 beats/min. Transplacental treatment strategies are aimed at preventing or modulating these risk factors. Maternal administration of dexamethasone to mitigate or prevent concomitant myocardial inflammation, in combination with beta-stimulation for persistent fetal bradycardia < 55 beats/min to increase fetal cardiac output, has resulted in significantly improved fetal and neonatal outcomes without reversing CAVB.

Although extremely rare, rupture of an unscarred gravid uterus poses significant morbidity and mortality to both fetus and mother. In the past, loss of uterine contraction was thought to be characteristic of uterine rupture, while recent evidence shows that uterine contraction pattern is not associated with uterine rupture. We report two cases of rupture in the unscarred term uterus. Both patients were multiparous and denied any past medical complications, previous cesarean delivery or myomectomy. Uterine rupture occurred in the latent phase of labor at 1 cm dilation (Case 1) and during an intravenous oxytocin infusion after three doses of intravaginal misoprostol (Case 2). Case 2 required cesarean hysterectomy and blood transfusion. Case 1 was monitored with an external tocodynamometer, while Case 2 was monitored with an internal pressure transducer. External monitoring demonstrated the classic sign of complete loss of uterine tone. In contrast, internal monitoring demonstrated an increase in uterine resting tone. Both techniques revealed a stepwise gradual decrease in contraction amplitude followed by sudden onset of profound and prolonged fetal bradycardia (staircase sign). In cases of uterine rupture, differing baseline characteristics between contraction patterns were dependent on uterine monitoring technique. In both techniques a stepwise gradual decrease in contraction amplitude was followed by prolonged fetal bradycardia.

The occurrence of double aneuploidy is a relatively rare phenomenon. The clinical presentations are variable depending on the predominating aneuploidy or a combination effect of both. We report the cytogenetic data on products of conception from miscarriages over a period of 5 years. A total of 403 miscarriages were karyotyped and the tissues were villi in all cases. Of 403 cases, 54 cases with single aneuploidy and 2 cases of first-trimester miscarriages with double trisomies were found. These 2 cases with the karyotypes of 48,XXY,+15 and 48,XX,+5,+7 were cited for the first time in this study., ((c) 2008 S. Karger AG, Basel.)

Background: The antiepileptic drugs (AEDs) phenytoin, phenobarbital, dimethadione, and carbamazepine cause a similar pattern of malformations in humans, with an increased risk after polytherapy. The teratogenicity has been linked to cardiac rhythm disturbances and hypoxic damage as a consequence of their common potential to inhibit a specific potassium ion current (IKr). The IKr is of major importance for embryonic cardiac repolarization and rhythm regulation. This study investigated whether these AEDs cause irregular rhythm and if various combinations of AEDs result in higher arrhythmia risk than exposure to a single AED., Methods: The effects on heart rhythm of a single AED (monotherapy), and of various combinations (polytherapy) of AEDs, in gestational day 10 C57BL mouse embryos in culture were analyzed and graphically illustrated during a 25 s recording with a digitalization technique., Results: All of the studied AEDs caused increased intervals between heartbeats (resulting in bradycardia) and large variations in the interval between heartbeats (resulting in irregular rhythm) in a concentration-dependent manner in cultured mouse embryos. Dimethadione caused irregular rhythm at concentrations within and phenytoin slightly above the therapeutic ranges. Polytherapy resulted in more substantial prolongation of the mean interval between heartbeats (>60 ms) than monotherapy at clinically relevant concentrations., Conclusions: The results suggest that polytherapy more than monotherapy causes substantial prolongation of the cardiac repolarization, a marker associated with high risk of developing irregular rhythm during longer exposure periods (days to months). This supports the idea that the increased risk for malformations following polytherapy is linked to an increased risk for cardiac rhythm disturbances., (2007 Wiley-Liss, Inc.)

Background: Identifying molecular pathways regulating the development of pacemaking and coordinated heartbeat is crucial for a comprehensive mechanistic understanding of arrhythmia-related diseases. Elucidation of these pathways has been complicated mainly by an insufficient definition of the developmental structures involved in these processes and the unavailability of animal models specifically targeting the relevant tissues. Here, we report on a highly restricted expression pattern of the homeodomain transcription factor Shox2 in the sinus venosus myocardium, including the sinoatrial nodal region and the venous valves., Methods and Results: To investigate its function in vivo, we have generated mouse lines carrying a targeted mutation of the Shox2 gene. Although heterozygous animals did not exhibit obvious defects, homozygosity of the targeted allele led to embryonic lethality at 11.5 to 13.5 dpc. Shox2-/- embryos exhibited severe hypoplasia of the sinus venosus myocardium in the posterior heart field, including the sinoatrial nodal region and venous valves. We furthermore demonstrate aberrant expression of connexin 40 and connexin 43 and the transcription factor Nkx2.5 in vivo specifically within the sinoatrial nodal region and show that Shox2 deficiency interferes with pacemaking function in zebrafish embryos., Conclusions: From these results, we postulate a critical function of Shox2 in the recruitment of sinus venosus myocardium comprising the sinoatrial nodal region.

Long QT Syndrome (LQTS) is a cardiac channelopathy characterized by prolonged ventricular repolarization and increased risk to sudden death secondary to ventricular dysrrhythmias. Was the first cardiac channelopathy described and is probably the best understood. After a decade of the sentinel identification of ion channel mutation in LQTS, genotype-phenotype correlations have been developed along with important improvement in risk stratification and genetic guided-treatment. Genetic screening has shown that LQTS is more frequent than expected and interestingly, ethnic specific polymorphism conferring increased susceptibility to drug induced QT prolongation and torsades de pointes have been identified. A better understanding of ventricular arrhythmias as an adverse effect of ion channel binding drugs, allow the development of more safety formulas and better control of this public health problem. Progress in understanding the molecular basis of LQTS has been remarkable; eight different genes have been identified, however still 25% of patients remain genotype-negative. This article is an overview of the main LQTS knowledge developed during the last years.

Objective: We present a case of fetal complete atrioventricular block, diagnosed by the M mode of two-dimensional ultrasound, that was complicated with polyhydramnios and bilateral hydrocele., Case Report: The fetus was delivered at 38 weeks' gestation by caesarean section. Postpartum autoimmune survey disclosed positive anti-Ro antibodies (SS-A) for both the mother and the newborn. Severe neonatal bradycardia with complete atrioventricular block was identified., Conclusion: Antenatal evaluation for a maternal history of autoimmune disease (especially systemic lupus erythematosus) and prevention of fetal bradycardia by reducing immune-mediated injuries on the cardiac conduction system are important.

Prevalence of congenital heart disease increases with nuchal translucency (NT) thickness. First-trimester fetal bradycardia may result from heart block associated with complex congenital heart disease. We report two cases detected in the first trimester of pregnancy, in which both fetuses showed an increased nuchal translucency and bradycardia. Fetal karyotype was normal in both fetuses. First-trimester fetal echocardiography was performed and, in both cases, complex congenital heart disease was diagnosed. We discuss the added role of fetal heart rate in first-trimester ultrasound screening, in fetuses with increased nuchal translucency and normal karyotype. We stress, as well, the importance of echocardiography performed in the first trimester as a potential tool for early diagnosis in selected cases., (Copyright 2005 John Wiley & Sons, Ltd)

Objectives: To examine intrapartum fetal heart rate (FHR) patterns in the presence of velamentous cord insertion (VCI)., Methods: The site of cord insertion was determined in 1460 women on antenatal ultrasonographic and postnatal examinations. Each of 24 women with pregnancies complicated with VCI was matched at the onset of labor with 10 women who had a normal pregnancy, and FHR patterns were analyzed for both cases and controls., Results: Compared with controls, cases of variable decelerations with no accelerations (VDNA) during the first and second stages of labor were more frequent in women with VCI (first stage: 25% vs. 5.1%, second stage: 65.0% vs. 21.7%, P < 0.001). The adjusted odds ratio associated with VDNA occurrence in women with VCI was 3.83 (95% confidence interval [CI]: 1.51-9.72, P = 0.005). The mean odds ratio associated with length of aberrant vessels in women with VCI plus VDNA was 1.38 (95% CI: 1.04-1.83, P = 0.026)., Conclusion: Pregnancies complicated with VCI are associated with a higher rate of VDNA.

Background: Cardiogram signal amplitude is a key index of hypertrophy but has not been investigated extensively in utero. In this study, magnetocardiography was used to assess P and QRS amplitude in normal subjects and subjects with fetal arrhythmia., Methods and Results: The study cohort consisted of 68 normal fetuses and 25 with various arrhythmias: 9 reentrant supraventricular tachycardia (SVT), 2 ventricular tachycardia (VT), 2 sinus tachycardia, 2 blocked atrial bigeminy, 2 congenital second-degree atrioventricular (AV) block, and 8 congenital complete AV block. Subjects with congenital AV block, all presenting with bradycardia, showed large QRS amplitude, exceedingly large P-wave amplitude, and long P-wave duration. The 2 subjects with VT, both with poor ventricular function, also exhibited large P waves. SVT was associated with only moderate signal amplitude elevation., Conclusions: The data imply that AV block in utero is accompanied by hypertrophy, which is more pronounced for the atria than the ventricles. We hypothesize that the hypertrophy results from a compensatory response associated with regulation of cardiac output and is likely to be observable in other arrhythmias and disease states. Magnetocardiography may be more sensitive than fetal echocardiography for detection of atrial hypertrophy in utero.

Background: Prenatal surgery for congenital anomalies can prevent fetal demise or alter the course of organ development, resulting in a more favorable condition at birth. The indications for fetal surgery continue to expand, yet little is known about the acute sequelae of fetal surgery on the human cardiovascular system., Methods and Results: Echocardiography was used to evaluate the heart before, during, and early after fetal surgery for congenital anomalies, including repair of myelomeningocele (MMC, n=51), resection of intrathoracic masses (ITM, n=15), tracheal occlusion for congenital diaphragmatic hernia (CDH, n=13), and resection of sacrococcygeal teratoma (SCT, n=4). Fetuses with MMC all had normal cardiovascular systems entering into fetal surgery, whereas those with ITM, CDH, and SCT all exhibited secondary cardiovascular sequelae of the anomaly present. At fetal surgery, heart rate increased acutely, and combined cardiac output diminished at the time of fetal incision for all groups including those with MMC, which suggests diminished stroke volume. Ventricular dysfunction and valvular dysfunction were identified in all groups, as was acute constriction of the ductus arteriosus. Fetuses with ITM and SCT had the most significant changes at surgery., Conclusions: Acute cardiovascular changes take place during fetal surgery that are likely a consequence of the physiology of the anomaly and the general effects of surgical stress, tocolytic agents, and anesthesia. Echocardiographic monitoring during fetal surgery is an important adjunct in the management of these patients.

Background: The aim of this study was to establish the prognostic import of spontaneous fetal heart-rate deceleration, a sign of fetal distress., Methods: This retrospective study enrolled 169 patients with fetal heart-rate deceleration treated at Shin-Kong Wu Ho Su Memorial Hospital from 1 January 1998 to 24 November 2000. Reviewed variables included type of fetal heart-rate irregularity (including early, variable, late, and spontaneous variants), neonatal outcome, Doppler results, gestational age and weight at birth, and amniotic fluid index., Results: The spontaneous form of fetal heart-rate deceleration was determined for 11 of the 169 patients (6.5%) diagnosed with fetal heart-rate deceleration, with a 5-min Apgar score below 7 observed for 5 (45.5%) of these subjects, and neonatal complications for 9 (81.8%). Mean gestational age was 32.2+/-3.8 weeks; mean birth weight was 1,560+/-723.9 g. Spontaneous deceleration has a sensitivity of 29%, specificity of 99%, positive predictive value of 81.8%, and negative predictive value of 86.1%., Conclusion: Although of the different fetal heart-rate deceleration types the spontaneous variant has the lowest incidence rate, the complication and mortality rates are highest and it is also associated with lower birth weight and higher incidence of pre-term labor. Failure of the fetus to cope with the compromised placental flow and uterine compression resulting from oligohydramnios may be fundamental to the etiology of spontaneous fetal-heart rate deceleration. Once diagnosed, Doppler ultrasound may be used to assess placental-vessel flow. Emergency treatment may be mandatory if deterioration is noted.

Background: The purpose of this study was to evaluate the clinical outcome of fetuses with bradyarrhythmias or complete heart block (CHB) in the setting of fetal structural heart disease (CHD) or of maternal collagenosis with and without treatment., Methods: A retrospective analysis of echocardiographic studies performed in 14 fetuses (mean gestational age 25.5, range 19 - 36 weeks) referred for exclusion or diagnosis of bradyarrhytmias was performed. Maternal SS-A/Ro and SS-B/La antibodies were measured by ELISA., Results: 14 fetuses showed bradyarrhythmias or complete heart block in combination with severe cardiac malformations (n = 7) or with positive maternal antibodies (n = 7). Only one of the fetuses with CHD survived infancy as opposed to 5/7 fetuses with complete atrioventricular block in the setting of maternal collagenosis. Maternal treatment with corticosteroids did not seem to influence the rhythm disorder., Conclusion: Fetal echography is a safe method to detect bradyarrhythmias or complete atrioventricular block. When associated with structural heart defects, fetal prognosis is poorer than in combination with maternal collagenosis.

Congenital heart block (CHB) associated with maternal anti-SSA/SSB antibodies: a report of four cases. CHB detected in utero is strongly associated with maternal antibodies to SSA (Ro) and SSB (La). Their pathogenic role in the development of CHB has been established in several studies. The mothers of affected infants frequently had autoimmune disease (systemic lupus erythematosus, Sjögren's syndrome) or were entirely asymptomatic. It is very difficult to identify pregnant asymptomatic mothers carrying anti-SSA/SSB antibodies. We report four cases of infants born to asymptomatic mothers with anti-SSA/SSB antibodies, three of them developed isolated congenital cardiac heart block and one with no evidence of CHB. All three CHB are detected during pregnancy between 16 and 24 weeks of gestation. All maternal sera contained antibodies to SSA alone or the both SSA and SSB. Three of four subsequent pregnancies were complicated by heart block. One child affected died in utero. While the two other newborns with CHB required pacemaker insertion during the first 3 months of life. Although the association of anti-SSA/SSB with CHB is widely accepted, the precise mechanism by which these antibodies cause cardiac conduction abnormalities remains to be defined. Antibodies to SSA/SSB have been proposed to be a serologic marker for neonatal lupus syndrome and CHB. Fetal and neonatal diseases are presumed to be due to the transplacental passage of these IgG autoantibodies from the mother into the fetal circulation. Since these antibodies may have a pathogenic role in CHB, screening of infants with isolated CHB or neonatal lupus and their mothers for the presence of anti-SSA and anti-SSB is strongly recommended.

Objective: To determine the relationship between decision to delivery interval and perinatal outcome in severe placental abruption., Design: A case-control study., Setting: Large inner city teaching hospital., Methods: Retrospective case note review of pregnancies terminated following severe placental aburption and fetal bradycardia. One year paediatric follow up by case note review or postal questionnaire. The differences in outcome (death or cerebral palsy) were examined using non-parametric and univariate analysis for the following time periods--times from onset of symptoms to delivery, onset of symptoms to admission, admission to delivery, onset bradycardia to delivery and decision to delivery interval., Main Outcome Measures: Prenatal death or survival with cerebral palsy., Results: Thirty-three women with singleton pregnancies over 28 weeks of gestation, admitted with clinically overt placental abruption, where delivery was effected for fetal bradycardia. Eleven of the pregnancies had a poor outcome (cases), eight infants died and three surviving infants have cerebral palsy. Twenty-two pregnancies had a good outcome (controls): survival with no developmental delay. No statistically significant relationship was found between maternal age, parity, gestation, or birthweight and a poor outcome. A statistically significant relationship between time from decision to delivery was identified (P = 0.02, Mann-Whitney U test). The results of a univariate logistic regression for this variable suggest that the odds ratio of a poor outcome for delivery at 20 minutes compared with 30 minutes is 0.44 (95% CI 0.22-0.86). Fifty-five percent of infants were delivered within 20 minutes of the decision to deliver. Serious maternal morbidity was rare., Conclusion: In this small study of severe placental abruption complicated by fetal bradycardia, a decision to delivery interval of 20 minutes or less was associated with substantially reduced neonatal morbidity and mortality.

Objective: To correlate the presence of baseline variability and the duration of a prolonged deceleration/bradycardia in intrapartum fetal heart rate (FHR) tracings with the development of neonatal acidemia., Methods: We identified 186 patients with term gestations who had continuous electronic fetal monitoring for at least 2 hours before delivery, with an identified bradycardia during that period. Each patient had umbilical artery cord analysis done and delivery within 30 minutes of that bradycardia. One investigator blinded to the cord gas outcome reviewed the last 2 hours of the tracing using the National Institute of Child Health and Human Development guidelines for FHR monitoring. We assessed the presence or absence of variability before the bradycardia and recovery or no recovery of the bradycardia and placed the patients into four groups. Group 1 (128 patients) with normal variability and recovery, group 2 (40 patients) with normal variability and no recovery, group 3 (nine patients) with decreased variability and recovery, and group 4 (nine patients) with decreased variability and no recovery. We compared the incidence of neonatal acidosis defined as a pH of less than 7.0 at birth among the four groups. The relationship between the various groups was assessed using analysis of variance and the chi(2) test. In addition, a multiple logistic regression model was developed with the parameters of amplitude and recovery used to predict pH at birth., Results: The presence of decreased variability and no recovery of the FHR of a bradycardia was associated with the lowest pH 6.83 +/- 0.16 and a 78% incidence of significant acidosis. Decreased variability before FHR bradycardia was the FHR parameter significantly correlated with low pH., Conclusion: The most significant factor predicting the development of pathologic neonatal acidemia and indicating the need for urgent delivery in the presence of a bradycardia is decreased variability before the bradycardia.

Objective: Recent evidence in literature shows that the long QT syndrome accounts for a fraction of the sudden infant death syndrome. Newborn infants with prolongation of the Q-T interval often show sinus bradycardia, which led us to test whether children who were diagnosed with long QT syndrome also show sinus bradycardia in the cardiotocogram before birth., Study Design: We identified 18 children who were born from singleton pregnancies at or near term in whom long QT syndrome (corrected QT interval, >0.440 second) was diagnosed after birth or in childhood. Cardiograms during pregnancy and delivery were available from 17 of the 18 children., Results: The cardiotocogram showed persistent fetal sinus bradycardia (baseline heart rate permanently below 120 beats/min) in 12 of 17 fetuses (71%) with long QT syndrome. Two fetuses had additional intermittent tachyarrhythmias., Conclusion: Sinus bradycardia in the cardiotocogram during delivery or in pregnancy may indicate long QT syndrome in the fetus. Postnatal electrocardiography should be performed in these children to rule out or confirm a prolongation of the Q-T interval.

Background: Phenytoin (PHT) teratogenicity has been related to embryonic arrhythmia due to the capacity of PHT to block I(K) channels pharmacologically, resulting in hypoxia-reoxygenation damage. The aim of this study was to further elucidate the proposed mechanism., Methods: Pregnant CD-1 mice were given PHT (85 mg/kg) or saline intraperitoneally on gestational days 10-11. Embryonic heart rhythm and presence of hemorrhage in orofacial region was recorded on day 12, fetuses were examined for malformations on day 18. Embryonic heart rate was also recorded on individual days after dosing days 9-16. In addition, PHT was given at doses of 10, 25, or 85 mg/kg on day 12 for analysis of plasma concentrations., Results: PTH-induced bradycardia and arrhythmia in approximately 20% of the embryos, 48% showed hemorrhage in the orofacial region; 39% of the fetuses had cleft palate. The region in which hemorrhages were visible in the embryo corresponded with the region where tissue deficiency (cleft palate) was visible in the fetus at term. None of the controls showed hemorrhages, dysrhythmia, or cleft palate. PHT affected embryonic heart rates on days 9-13, but not on days 14-16. Single dose administration on day 12, the most sensitive day, resulted in a dose-dependent decrease in embryonic heart rate (12-34%). Embryonic arrhythmia occurred at 25 and 85, but not at 10 mg/kg or in the controls. Mean maternal free plasma concentrations were 6 and 14 micromol/L in the 10- and 25-mg/kg groups, respectively., Conclusions: PHT-induced cleft palate was preceded by embryonic dysrhythmia and hemorrhage in the orofacial region. Embryonic heart rhythm was phase specifically affected, as described for selective I(Kr) channel blockers, at clinically relevant concentrations. The results support the idea that PHT teratogenicity is a consequence of pharmacologically induced dysrhythmia and hypoxia-related damage., (Copyright 2001 Wiley-Liss, Inc.)

Introduction: Red cell autoantibodies are very rarely observed in pregnant women. We report one case related to the presence of a lupus anticoagulant., Exegesis: A 32-year-old woman had a history of two intrauterine deaths that had occurred at weeks 32 and 33, respectively. Due to the presence of a lupus anticoagulant, prednisone (20 mg/day) and subcutaneous calcium heparin were administered during her third pregnancy. The direct antiglobulin test remained positive throughout the pregnancy; however, hemolysis could not be detected. Caesarean section was done in emergency at week 29, due to fetal bradycardia related to severe fetal hemolysis., Conclusion: When autoimmune hemolysis occurs during pregnancy, risks for the fetus increase with the severity of hemolysis in the mother. It is thought that child mortality reflects the existence of anemia, rather than the existence of hemolysis. Our observation suggests that severe fetal hemolysis may occur, despite the absence of hemolysis in the mother.

Several clinical investigations on the course and outcome of pregnancies following cordocentesis have mentioned the occurrence of fetal bradycardia at the time of umbilical cord puncture. The prognostic impact of this common complication has remained controversial. Our purpose was to investigate the prevalence and the short-term and long-term consequences of fetal bradycardia associated with cordocentesis. This study included all 339 cordocenteses performed in 290 fetuses at the Division of Prenatal Diagnosis and Therapy, University of Vienna, between 1991 and 1994. Clinically significant bradycardia was defined as a drop in the heart rate to less than 100 beats/min for a period of > or = 60 s. Bradycardia during or immediately after cordocentesis was observed in 13 cases (3.8 per cent). The fetal/neonatal loss rate per procedure was 61.5 per cent (8/13) in cases with bradycardia and 3.1 per cent (10/326) in those without bradycardia (P < 0.001). Early gestational age and hydrops fetalis correlated significantly with the development of bradycardia at cordocentesis. The other risk groups, including fetuses with intrauterine growth retardation, the puncture site, and the number of puncture attempts did not correlate with fetal bradycardia. Our results indicate that prolonged fetal bradycardia during or after cordocentesis is characteristic of a group of fetuses with an especially unfavourable prognosis.

Two term-pregnant women presented in the obstetric unit with marked diaphoresis and tremulousness. Fetal heart rate monitoring revealed severe bradycardia. Both mothers had blood glucose levels consistent with the diagnosis of hypoglycemia. In both cases the fetal heart rate normalized with improvement in the mothers' glycemic state. The presence of maternal hypoglycemia should always be considered as a potential cause of fetal bradycardia.

Amnioinfusion is a relatively new technique with a variety of uses. Its most common application is the treatment of variable decelerations in the fetal heart rate during labor. By artificially increasing the amniotic fluid volume, the umbilical cord is better protected from compression. Amnioinfusion can represent the difference between operative intervention and spontaneous vaginal delivery. This simple, inexpensive technique appears to pose little risk and warrants consideration for the properly selected patient.

A predictable late embryonic bradycardia (relative to normal White Leghorn chickens) has been documented in chicken strains with C locus mutations. The basis of the bradycardia remains unknown but clearly is related to a mutation at the C locus, which contains the structural gene for tyrosinase. When compared with the heart rate of normal White Leghorns (approximately 295-305 beats/min from day 8 to day 20 of incubation), ca/ca and other C locus mutants showed a 10-12% reduction in heart rate during the last 4 days of incubation. Embryonic mortality occurred in both mutant and normal strains at an equivalent rate (approximately 23%); a significant bradycardia (when compared with surviving embryos of the same strain) developed on the day before death in White Leghorn but not mutant strains. The bradycardia did not affect embryonic oxygen consumption (approximately 0.2 ml O2.egg-1.min-1 at day 14 and 0.4 ml O2.egg-1.min-1 at day 20), which showed only minor differences between strains that can be attributed to differences in embryonic mass on days 16-20.

Umbilical artery flow curves were obtained by Doppler ultrasonography before, during, and after episodes of fetal bradycardia in the active stage of labor in 6 women. Between 126 and 1,607 Doppler wave forms were analyzed for each patient. During the periods of bradycardia all the umbilical artery resistance flow parameters increased (p < 0.00001). The increase in resistance did not precede the change in heart rate. This study presents an accurate and reproducible method for continuous evaluation of the changes in the impedance of fetal blood flow during fetal heart rate changes, thereby enabling detailed assessment of circulatory disturbances occurring during labor and delivery.

An 18-year follow-up study was made of 62 males delivered by forceps and 38 by vacuum extraction in 1962-63. The obstetrical data are compared with the medical and psychological military draft board examinations. The mortality and morbidity rates were not significantly different from those of the total cohort of Norwegian conscripts, either in the forceps or in the vacuum group. Rotation of the fetal head with Kielland's forceps in midcavity extractions did not adversely affect the late results. A significantly elevated mean intelligence score was found in the forceps group, while the vacuum group did not differ from the national average.