Risk Factors Associated with Intraventricular Hemorrhage in Preterm Infants with ≤28 Weeks Gestational Age.

OBJECTIVE: To identify obstetric and neonatal risk factors associated with the development of germinal matrix-intraventricular hemorrhage (GM-IVH) in high-risk preterm neonates. METHODS AND PATIENTS: Data from 279 preterm infants (246 mothers) with a gestational age≤28+0 weeks admitted to our NICU between January 2004 and December 2009 were analyzed retrospectively. Occurrence of (GM-IVH) was diagnosed by using ultrasound and important clinical variables were extracted from the patient charts. Infants were divided into 2 groups: GM-IVH and non-GM-IVH. To account for multiple gestation, generalized estimation equations (GEE) were used for univariate analysis and for the evaluation of independent risk factors. RESULTS: A low 5-min APGAR-Score, multiple birth, low arterial blood pressure at NICU admission, hypercapnia during the first 72 h of life in life and absence of any antenatal corticosteroids were found to be significant independent risk factors in the development of GM-IVH. CONCLUSION: Preterm infants with low arterial blood pressure, absence of antenatal corticosteroids, low 5-min APGAR-Score, higher paCO2 within the first 3 days of life and multiple gestation were at higher risk to develop GM-IVH. Avoiding these risk factors may help to decrease the rate of GM-IVH.

[The Wolf-Hirschhorn Syndrome]. / Das Wolf-Hirschhorn Syndrom.

Wolf-Hirschhorn syndrome (WHS) represents a complex developmental disorder characterized by craniofacial dysmorphism, short stature, hypotonia, psychomotor retardation and seizures caused by a terminal deletion of the short arm of chromosome 4. Depending on the extent of the deletion, variable midline defects, abnormalities of the skeletal or urogenital system as well as the central nervous system are observed. Approximately 1/3 of the infants will die in the first year of life even though survival for more than 30 years has been reported. Due to current high quality standards of ultrasonography, WHS can often be diagnosed prenatally. We present a clinical case and provide an overview of the current literature.

The Cause of Acute Respiratory Failure Predicts the Outcome of Noninvasive Ventilation in Immunocompromised Children.

BACKGROUND: Noninvasive ventilation (NIV) may be superior to conventional therapy in immunocompromised children with respiratory failure. METHODS: Mortality, success rate, prognostic factors and side effects of NIV for acute respiratory failure (ARF) were investigated retrospectively in 41 in children with primary immunodeficiency, after stem cell transplantation or chemotherapy for oncologic disease. RESULTS: In 11/41 (27%) children invasive ventilation was avoided and patients were discharged from ICU. In children with NIV failure ICU-mortality was 19/30 (63%). 8/11 (72%) children with NIV success had recurrence of ARF after 27 days. Only 4/11 (36%) children with first episode NIV success and 8/30 (27%) with NIV failure survived to hospital discharge. Lower FiO2, SpO2/FiO2 and blood culture positive bacterial sepsis were predictive for NIV success, while fungal sepsis or culture negative ARF were predictive for NIV failure. We observed catecholamine treatment in 14/41 (34%), pneumothorax in 2/41 (5%), mediastinal emphysema in 3/41 (7%), a life threatening nasopharyngeal hemorrhage and need for resuscitation during intubation in 5/41 (12%) NIV-episodes. CONCLUSIONS: The prognosis of ARF in immunocompromised children remains guarded independent of initial success or failure of NIV due to a high rate of recurrent ARF. Reversible causes like bacterial sepsis had a higher NIV response rate. Relevant side effects of NIV were observed.

Automated adjustments of inspired fraction of oxygen to avoid hypoxemia and hyperoxemia in neonates - a systematic review on clinical studies.

Supplemental oxygen is commonly provided during transition of neonates immediately after birth. Whereas an initial FiO2 of 0.21 is now recommended to stabilize full-term infants in the delivery room, the best FiO2 to start resuscitation of the very low birth weight infant (VLBWI) immediately after delivery is currently not known. Recent recommendations include the use of pulse oximetry to titrate the use of supplemental oxygen. As reference values for pulse oximetry during the first minutes of life have become available, automated FiO2-adjustments are feasible and may be very useful for delivery room care to limit oxygen exposure. Beyond neonatal transition, preterm infants in the neonatal intensive care unit (NICU) commonly require supplemental oxygen to avoid hypoxemia, especially VLBWI receiving respiratory support because of poor respiratory drive and/or lung disease. For respiratory care of newborn infants in the NICU automated FiO2-adjustment systems have been developed and have been studied in preterm infants for limited time frames using short-term physiological outcomes. These studies could demonstrate short-term benefits such as more stable arterial oxygen saturation. Recent clinical trials have shown that oxygen targeting may significantly affect mortality and morbidity. Therefore, randomized controlled trials are needed to study the effects of automated FiO2-adjustment on long-term outcomes to prove possible benefits on survival, the rate of retino-pathy of prematurity and on neuro-development-al outcome.

[Treatment of neonatal asphyxia with a special focus on therapeutic hypothermia]. / Behandlung der neonatalen Asphyxie unter besonderer Berücksichtigung der therapeutischen Hypothermie.

In recent years the treatment of newborns for neonatal asphyxia has experienced a lot of new developments. A major milestone were the positive results of various trials for prophylactic treatment of hypoxic-ischemic encephalopathy by moderate cooling of the child or of his head. With this paper we attempt to provide a consented guideline to aid in the treatment decision for affected newborns and thus achieve a more homogeneous treatment strategy throughout Germany.

[Neurodevelopmental outcome of very low birth weight infants born at the Perinatal Centre in Ulm, Germany]. / Entwicklungsneurologische Nachuntersuchung von sehr unreifen Frühgeborenen im Perinatalzentrum Ulm.

BACKGROUND: Since 2006 an assessment of the neurodevelopmental outcome of very low birth weight infants (VLBWI) at a corrected age of 2 years is mandatory for every perinatal centre in Germany. The aim of our study was to check how complete these assessments were performed in our population of infants born at our perinatal centre and receiving treatment within our local neonatal network. Furthermore, the data obtained will be used for prenatal consultations. Another objective was to identify risk factors for adverse neurodevelopmental outcomes. METHODS: All VLBWI were invited for a follow-up exam using the Bayley Scales of Infant Development II (BSID-II) or III (BSID-III), or Griffiths Mental Developmental Scales) at 2 years corrected age. The results of children assessed by other institutions were collected. RESULTS: 142 (69.3%) of the 205 VLBWI, born and finally discharged alive at the perinatal centre in Ulm were assessed at a median (minimum - maximum) corrected age of 23 (18-27) months. The BSID-II Psychomotor Development Index (PDI) 91 was (< 50-128) (n=115), the BSID-II Mental Development Index (MDI) was 87 (< 50-134) (n=96), BSID-III MDI 95 (60-112) (n=29) and the Griffiths Score was 93 (67-140) (n=17). Severe disability was diagnosed in 36 (25.4%) of the children studied. Gestational age and higher grade intraventricular haemorrhage were associated independently with severe disability. CONCLUSIONS: It is very difficult to achieve a high rate of follow-up examinations in preterm infants <1,500 g in a neonatal network. Severe impairment in VLBWI is not rare. Improving neurodevelopmental outcome remains a challenge.

[Mortality of extremely low birthweight infants - large differences between quality assurance data and the national birth/death registry]. / Mortalität sehr unreifer Frühgeborener - Erhebliche Diskrepanz zwischen Neonatalerhebung und amtlicher Geburten-/Sterbestatistik.

BACKGROUND: To evaluate neonatal outcome, the German neonatal quality assurance dataset is often used. However, a systematic bias may occur, as not all live births are registered in this dataset. The aim of our study was to evaluate the magnitude of this systematic error by comparing this dataset to the national birth/death registry. METHODS: The summary statistics of live births and deaths with a birthweight <1 500 g from the quality assurance datasets 2007-2009 of 5 German States (Baden-Württemberg, Bavaria, Hesse, Lower-Saxony and North Rhine-Westfalia) were compared with the dataset from the national birth/death registry. RESULTS: Our analysis included 68% of the German birth cohort 2007-2009. The quality assurance dataset included 1 151 of 1 716 neonatal deaths (67.1%) in infants with a birthweight <1,000 g registered within the national birth/death registry; 565 deaths were missing. A total of 277 of 303 deaths (94.1%) with a birthweight 1,000-1,499 g were registered; 26 deaths were missing. In the state of Baden-Württemberg up to 11% more infants were registered in the quality assurance dataset than in the national registry, but an average of 36 neonatal deaths/year with a birthweight <1,000 g were missing (63.4% registration rate). CONCLUSION: This analysis shows that the quality assurance data miss more than 1/3 of deaths in extremely low birthweight infants. Transfers between hospitals may result in multiple data entries and additional bias. Comparing outcome statistics based on the neonatal quality assurance dataset may lead to a substantial systematic error. Linkage to national birth and death certificates and/or to the perinatal dataset is urgently needed.

Delivery room management of very low birth weight infants in Germany, Austria and Switzerland--a comparison of protocols.

BACKGROUND: Surveys from the USA, Australia and Spain have shown significant inter-institutional variation in delivery room (DR) management of very low birth weight infants (VLBWI, <1500g) at birth, despite regularly updated international guidelines. OBJECTIVE: To investigate protocols for DR management of VLBWI in Germany, Austria and Switzerland and to compare these with the 2005 ILCOR guidelines. METHODS: DR management protocols were surveyed in a prospective, questionnaire-based survey in 2008. Results were compared between countries and between academic and non-academic units. Protocols were compared to the 2005 ILCOR guidelines. RESULTS: In total, 190/249 units (76%) replied. Protocols for DR management existed in 94% of units. Statistically significant differences between countries were found regarding provision of 24 hr in house neonatal service; presence of a designated resuscitation area; devices for respiratory support; use of pressure-controlled manual ventilation devices; volume control by respirator; and dosage of Surfactant. There were no statistically significant differences regarding application and monitoring of supplementary oxygen, or targeted saturation levels, or for the use of sustained inflations. Comparison of academic and non-academic hospitals showed no significant differences, apart from the targeted saturation levels (SpO2) at 10 min. of life. Comparison with ILCOR guidelines showed good adherence to the 2005 recommendations. SUMMARY: Delivery room management in German, Austrian and Swiss neonatal units was commonly based on written protocols. Only minor differences were found regarding the DR setup, devices used and the targeted ranges for SpO2 and FiO2. DR management was in good accordance with 2005 ILCOR guidelines, some units already incorporated evidence beyond the ILCOR statement into their routine practice.

Surgery without assistance in newborns and infants with hydrocephalus and neural tube defects.

Standard neurosurgical procedures for hydrocephalus and open neural tube defects in newborns and infants under 6 months of age were performed by a single neurosurgeon on his own without the help of an assistant or scrub nurse. The objective of this study was to assess the outcome of these procedures in terms of operating time, the presence of bacterial infection, and wound healing. Between 2001 and 2004, a total of 126 procedures were performed on 82 patients under 6 months of age. We observed 1 bacterial and 2 fungal infections. Two infections had already been detected at the beginning of the surgical procedure in cerebrospinal fluid (CSF) specimens obtained from children with Candida ventriculitis. The other infection occurred after leakage of CSF from a myelomeningocele 10 days after initial surgery. Our study suggests that excellent results can be achieved in standard neurosurgical procedures without assistance even in high-risk newborns and infants if resource or other constraints require such an unconventional approach.

Cardiac Depression in Pigs after Multiple Trauma - Characterization of Posttraumatic Structural and Functional Alterations.

The purpose of this study was to define the relationship between cardiac depression and morphological and immunological alterations in cardiac tissue after multiple trauma. However, the mechanistic basis of depressed cardiac function after trauma is still elusive. In a porcine polytrauma model including blunt chest trauma, liver laceration, femur fracture and haemorrhage serial trans-thoracic echocardiography was performed and correlated with cellular cardiac injury as well as with the occurrence of extracellular histones in serum. Postmortem analysis of heart tissue was performed 72 h after trauma. Ejection fraction and shortening fraction of the left ventricle were significantly impaired between 4 and 27 h after trauma. H-FABP, troponin I and extracellular histones were elevated early after trauma and returned to baseline after 24 and 48 h, respectively. Furthermore, increased nitrotyrosine and Il-1ß generation and apoptosis were identified in cardiac tissue after trauma. Main structural findings revealed alteration of connexin 43 (Cx43) and co-translocation of Cx43 and zonula occludens 1 to the cytosol, reduction of α-actinin and increase of desmin in cardiomyocytes after trauma. The cellular and subcellular events demonstrated in this report may for the first time explain molecular mechanisms associated with cardiac dysfunction after multiple trauma.

Delivery room management of extremely low birth weight infants: spontaneous breathing or intubation?

OBJECTIVE: To study the effect of two different delivery room (DR) policies on the rate of endotracheal intubation and mechanical ventilation (EI/MV) and short term morbidity in extremely low birth weight infants (ELBWI; <1000 g, >/=24 weeks). METHODS: Retrospective cohort study of 123 inborn ELBWIs born in 1994 and in 1996. DR policies have changed. Until 1994, ELBWIs were intubated immediately after delivery when presenting the slightest signs of respiratory distress or asphyxia after initial resuscitation using a face mask and a handbag. During 1995, the guidelines for respiratory support were changed. In 1996, continuous (15 to 20 seconds), pressure controlled (20 to 25 cm H2O) inflation of the lungs using a nasal pharyngeal tube, followed by continuous positive airway pressure (CPAP; 4 to 6 cm H2O) was applied to all ELBWIs immediately after delivery to establish a functional residual capacity and perhaps to avoid EI/MV. In addition to the changes in respiratory support, the prevention of conductive and evaporative heat loss was improved in 1996. For analysis of morbidity and mortality, infants were matched for gestational age and birth weight. RESULTS: The rate of EI/MV in the DR decreased from 84% in 1994 to 40% in 1996. In 1996, 25% of the ELBWIs were never intubated (7% in 1994), but 35% of the ELBWIs needed secondary EI/MV, primarily because of respiratory distress syndrome (RDS). Initial ventilator settings, ventilator days, mortality, and morbidity were not different between ELBWIs with EI/MV in the DR and infants with secondary EI/MV attributable to RDS in the intensive care unit. ELBWIs with no EI/MV that was caused by RDS had a lower morbidity (ie, bronchopulmonary dysplasia, intraventricular hemorrhage >grade 2 and/or periventricular leukomalacia), mortality, and fewer hospital days (mean: 79 vs 105 days). The incidence of gastrointestinal adverse effects like feeding intolerance or necrotizing enterocolitis was not increased in 1996. PaCO2 was significantly higher at admission to the neonatal unit in ELBWIs with CPAP in 1996 (54 +/- 15 mm Hg, 7.2 +/- 2.0 kPa) compared with infants with EI/MV in 1994 (38 +/- 11 mm Hg, 5.1 +/- 1. 5 kPa. A total of 26% of spontaneously breathing infants had hypercapnia (PaCO2 >/=60 mm Hg [8.0 kPa]), compared with 7% of infants with EI/MV in 1994. Within the first few hours of life, PaCO2 decreased to 46 (32 to 57) mm Hg (6.1 [4.3 to 7.6] kPa) in never intubated ELBWIs (n = 17), but increased to 70 (57 to 81) mm Hg (9.3 [7.6 to 10.8] kPa) in ELBWIs (n = 14) with RDS and secondary EI/MV (age 5.5 [1 to 44] hours). CONCLUSIONS: In our setting, the individualized intubation strategy in the DR restricted EI/MV to those ELBWIs who ultimately needed it, without increasing morbidity or mortality in infants with secondary EI/MV attributable to RDS. We speculate that an individualized intubation strategy of the ELBWI is superior to immediate intubation of all ELBWIs with slight signs of respiratory distress after birth.

The toxicity of beta-carotene.

The safety of beta-carotene, a widely distributed food colorant was assessed in tests with cells and in sub-chronic and chronic experiments with animals. Mutagenicity evaluations which included the standard Ames test and the micro-nucleus test of bone marrow cells from mice showed that beta-carotene exerted no mutagenic properties. Embryotoxicity studies in rats and rabbits showed that there was no evidence of embryotoxicity and a multiple generation study in rats showed that there was no interference with the reproductive function in rats given oral doses of up to 1000 mg/kg/day. Chronic toxicity was studied in a 2-year study with dogs in a toxicity/tumorigenicity study in rats and in a mouse carcinogenicity study. Histological findings in the livers of treated dogs and mice, but not in rats, included vacuolated cells with eccentric nuclei which were distributed in periportal areas and which were frequently associated with minimal lipid deposition. There was no evidence that the vacuolisation was dose-related. It was considered that the vacuolated cells were fat storage cells. There was no effect on the tumor profiles in the rat and the mouse studies.

Patient-triggered ventilation: a comparison of tidal volume and chestwall and abdominal motion as trigger signals.

Patient-triggered synchronized ventilation requires reliable and early detection of the infant's inspiratory effort. Several trigger methods have been developed that frequently lack the sensitivity to detect inspiration in small preterm infants (trigger failure), or show a high rate of breaths triggered by artifacts in the respiratory signal (autotrigger). The purpose of this study was to determine the effectiveness of the following trigger signals: abdominal movement sensed by a newly developed induction technique, chestwall motion detected by changes in transthoracic impedance, and tidal volume measured by anemometry at the endotracheal tube connector. Ten preterm infants (birth weight, 580-1,424 g; median weight, 943 g; study weight, 535-1,415 g; median weight, 838 g; gestation age, 26-32 weeks, median gestational age, 28 weeks, study age, 1-50 days, median study age, 11 days) were included in the study. A Sechrist SAVI ventilator was triggered by one of three signals: chestwall or abdominal movement, or tidal volume generated by the infants. Response time between beginning of inspiratory flow, the occurrence of the trigger signal (signal delay), and the onset of the triggered breath (trigger delay) were determined for each of the three signals. The signal response time was -13.5 msec (95% CI, -33 to -2 msec) for the abdominal movement signal, indicating that it started before inspiratory flow; 0.0 msec for the volume signal; and 44.0 msec (95% CI, 29-73 msec) for the chestwall signal (P < 0.002); this long delay was secondary to chestwall distortion and a subsequent delay in outward ribcage movement in many infants. The trigger delay for the abdominal signal was 90.0 msec (95% CI, 55-104 msec), 135.5 msec (95% CI: 82-186 msec) for the volume signal, and 176.5 msec (95% CI: 165-232 msec) for the chestwall signal, indicating that there was a difference in the rise time of signal voltage between the three methods (P < 0.01). The rate of autotriggered breaths was 3.2% (95% CI, 0.3-9.3%) when using the abdominal signal, 0.55% (95% CI, 0.0-2.1%) for the tidal volume signal, and 11.25% (95% CI, 0.5-27.8%) for the chestwall signal (P < 0.05). The incidence of trigger failure was low with all three signals and was not significantly different between the techniques. In summary, the chestwall signal had a long trigger delay and was highly susceptible to false triggering. It is, therefore, not a reliable trigger signal for synchronized mechanical ventilation in preterm infants. In contrast, tidal volume and abdominal movement signals had an acceptable trigger delay and a low rate of autotriggering, making them useful clinical trigger signals.

Influence of different methods of synchronized mechanical ventilation on ventilation, gas exchange, patient effort, and blood pressure fluctuations in premature neonates.

We studied the effects of two methods of synchronized mechanical ventilation [synchronized intermittent mandatory ventilation (SIMV) and assist/control (A/C)] on ventilation, gas exchange, patient effort, and arterial blood pressure (ABP) fluctuations. SIMV and A/C were applied in random order in 12 preterm neonates (gestational age, 29.7 +/- 2.3 weeks; birth weight, 1,217 +/- 402 g). We measured total (Vetot) and mechanical (Vemech) minute ventilation, spontaneous (Vtspont) and ventilator supported (Vtmech) tidal volume, transcutaneous oxygen saturation (SpO2), transcutaneous PO2 (TcPO2), and PCO2, (TcPCO2), mean airway pressure (Paw), phasic esophageal pressure deflections (Pe) as an estimate of inspiratory effort, mean arterial blood pressure (ABP), and beat-to-beat ABP fluctuations. The measurements obtained during conventional intermittent mandatory ventilation (IMV) were compared with the recordings during SIMV and A/C. To make the measurement conditions comparable and to prevent hyperventilation, peak inspiratory pressure was reduced during the A/C mode so that Vetot remained in the same range as during the IMV mode. Whereas Vetot was similar in all three conditions by study design, Vemech was larger during SIMV and A/C than during IMV. Vtmech increased during SIMV and by study design was smaller during A/C than during IMV. Pe decreased during SIMV and A/C compared with IMV, and Paw was higher during A/C than during IMV or SIMV. Beat-to-beat ABP fluctuations were reduced during SIMV and A/C compared with IMV and showed a close positive correlation with Pe changes. We conclude that SIMV increases Vemech and reduces Pe compared with IMV, resulting in smaller intrathoracic and ABP fluctuations. During A/C, a substantial portion of the spontaneous respiratory effort is shifted to the ventilator, resulting in a further decrease in Pe and ABP fluctuations.

Increased incidence of sighs (augmented inspiratory efforts) during synchronized intermittent mandatory ventilation (SIMV) in preterm neonates.

A reflex resulting in a deep, sigh-like inspiratory effort (augmented breath) is frequently triggered during synchronized mechanical ventilation in preterm infants. We studied the incidence of augmented inspiratory efforts and their effect on ventilation and lung compliance during conventional IMV and synchronized IMV (SIMV) in 15 preterm neonates (GA 26.7 +/- 1.5 wks (mean +/- SD), BW 925 +/- 222 g, age 1-8 days). Augmentation of spontaneous inspiratory effort was defined as an esophageal pressure deflection occurring coincident with a synchronized mechanical breath and exceeding the previous unassisted spontaneous effort by more than 50%. The incidence of augmented breaths was higher during SIMV (11.1 +/- 7.7%; P < 0.01) than during conventional IMV (5.1 +/- 6.1%). However, when the synchronized breaths were triggered late (200-300 msec) after the onset of inspiration, augmented breaths occurred no more frequently than during conventional IMV (6.0 +/- 4.7%). The incidence of augmented breaths correlated inversely with dynamic lung compliance (P = 0.014), but was not significantly influenced by a change in PEEP. Although inspiratory effort increased nearly three times during the augmented breaths, tidal volume increased only 12%. The change in tidal volume was limited because the augmented effort reached its maximal negativity only approximately 500 ms after the beginning of the synchronized, mechanical breath and at a time when the mechanical breath had already ended. For this reason the augmented effort did not contribute significantly to minute ventilation, but only prolonged inspiration. Dynamic lung compliance did not change significantly after an augmented breath. The results indicate that augmented inspiratory efforts are more common in preterm neonates ventilated with SIMV than with conventional IMV, but do not contribute significantly to ventilation.

Vitamin A teratogenicity and risk assessment in the macaque retinoid model.

Studies were performed in the cynomolgus monkey (Macaca fascicularis) to provide risk assessment information on safe dose levels of Vitamin A during human pregnancy. Vitamin A palmitate was orally administered at 7500 IU/kg (2.25 mg/kg) to 80 000 IU/kg (24 mg/kg) body weight during early pregnancy (gestation day [GD] 16-27). The results indicated a dose-related increase in exposure (AUC) to retinyl esters and retinoic acids (RA) (all-trans-RA, all-trans-4-oxo-RA, 13-cis-RA, 13-cis-4-oxo-RA). There was also a dose-related increase in abortion and malformation that affected typical retinoid target tissues in the embryo, including the craniofacial region, heart, and thymus. The NOAEL and LOAEL for structural malformations were 7500 IU/kg and 20 000 IU/kg (6 mg/kg), respectively. A companion study involving oral administration of 13-cis-RA during the same gestational period established the NOAEL for malformations at 0.5 mg/kg/day, which is close to the human therapeutic dose range (0.5 to 1.5 mg/kg/day) associated with retinoid embryopathy. Based on the known similarities in teratogenic susceptibility to 13-cis-RA, the monkey NOAEL for Vitamin A (7500 IU/kg) was used to estimate safe levels of this nutrient in humans applying a safety factor of 10. This approach yielded safe levels of Vitamin A during human pregnancy in the range of approximately 25 000 to 37 000 IU/day.

Cardiovascular alterations in rat fetuses exposed to calcium channel blockers.

Preclinical toxicologic investigation suggested that a new calcium channel blocker, Ro 40-5967, induced cardiovascular alterations in rat fetuses exposed to this agent during organogenesis. The present study was designed to investigate the hypothesis that calcium channel blockers in general induce cardiovascular malformations indicating a pharmacologic class effect. We studied three calcium channel blockers of different structure, nifedipine, diltiazem, and verapamil, along with the new agent. Pregnant rats were administered one of these calcium channel blockers during the period of cardiac morphogenesis and the offspring examined on day 20 of gestation for cardiovascular malformations. A low incidence of cardiovascular malformations was observed after exposure to each of the four calcium channel blockers, but this incidence was statistically significant only for verapamil and nifedipine. All four agents were associated with aortic arch branching variants, although significantly increased only for Ro 40-5967 and verapamil.