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Background Childhood obesity is often associated with non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in pediatrics. Methods This multi-center study analyzed liver echogenicity and liver enzymes in relation to obesity, age, gender and comorbidities. Data were collected using a standardized documentation software (APV) from 1.033 pediatric patients (age: 4–18 years, body mass index = BMI: 28–36 kg/m2, 50% boys) with overweight (BMI >90th percentile), obesity (BMI >97th percentile) or extreme obesity (BMI > 99.5th percentile) and obesity related comorbidities, especially NAFLD from 26 centers of Germany, Austria and Switzerland. Liver enzymes aspartate aminotransferase (AST), alanine-aminotransferase (ALT) and gamma glutamyltransferase (gammaGT) were evaluated using 2 cut-off values a) > 25 U/L and b) > 50 U/L. Multiple logistic regression models were used for statistical analysis. Results In total, 44% of the patients showed increased liver echogenicity. Liver enzymes > 25 U/L were present in 64% and > 50 U/L in 17%. Increased liver echogenicity was associated with elevated liver enzymes (> 25 U/L: odds ratio (OR) = 1.4, 95% CI: 1.1–1.9, P 50 U/L: OR = 3.5, 95% CI: 2.4–5.1, P P 14 years vs age P P 25 U/L: OR = 4.1, 95% CI: 2.4–6.9, P 50 U/L: OR = 18.5, 95% CI: 2.5–135, P 14 years vs age 50 U/L: OR = 1.9, 95% CI: 1.0–3.7, P > 0.05; boys vs girls > 25 U/L: OR = 3.1, 95% CI: 2.4–4.1, P 50 U/L: OR = 2.1, 95% CI: 1.5–2.9, P 50 U/L (OR = 4.4, 95% CI: 1.6–11.8, P 25 U/L (OR 1.6, 95% CI: 1.2–2.0, P Conclusions NAFLD is strongly related to extreme obesity in male adolescents. Moreover impaired glucose tolerance was observed in patients with elevated liver enzymes > 50 U/L, but arterial hypertension was only present in patients with moderately elevated liver enzymes > 25 U/L.

Nitroglycerin (GTN), often used in conditions of cardiovascular ischaemia, acts through the liberation of nitric oxide (NO) and the local concentration of NO in the tissue is responsible for any biological effect. However, little is known about the way in which the concentration of NO from GTN and other NO-donors is influenced by low oxygen tension in the target tissues. To evaluate the impact of changes in oxygen tension in the metabolism of NO-donors we measured exhaled NO in anaesthetized rabbits in vivo and expired NO and perfusate nitrite (NO(2)(-)) in buffer-perfused lungs in situ. The impact of acute hypoxia on NO formation from GTN, isosorbide-5-mononitrate (ISMN), dissolved authentic NO, NO(2)(-) and NO generated from endogenous NO-synthase (NOS) was studied in either model. Acute hypoxia drastically increased exhaled NO concentrations from all NO-donors studied, both in vivo and in the perfused lung. During similar conditions endogenous NO generation from NOS was strongly inhibited. The effects were most pronounced at less than 3% inspired oxygen. The mechanisms for the increased NO-formation during hypoxia seems to differ between GTN- and NO(2)(-)-derived NO. The former phenomenon is likely due to diminished breakdown of NO. In conclusion, hypoxic conditions preserve very high local NO concentrations generated from organic nitrates in vivo and we suggest that this might benefit preferential vasodilation in ischaemic tissue regions. Our findings point out the necessity to consider the influence of oxygen tension when studying the action of NO-donors.

Nitric oxide (NO) is continuously produced in the lung and can be measured in exhaled gas of different species. To investigate a possible neuro-humoral regulation of pulmonary NO production in vivo we injected veratrine, an activator of Na(+) channels known to activate the sympathoadrenal system, in anaesthetized, mechanically ventilated and laparotomized rabbits. Exhaled NO concentration increased by 38+/-3% when plasma adrenaline rose from 12.3+/-3.1 to 49.5+/-10.7 pmol ml(-1) in response to veratrine (500 microg kg(-1), i.v.). Pretreatment with atenolol, a beta(1)-adrenoceptor antagonist (1 mg kg(-1)), or bilateral ligation of adrenal blood vessels inhibited the increase in exhaled NO in response to veratrine. Atenolol also decreased basal NO, suggesting an endogenous regulation of pulmonary NO by adrenaline. Neither phentolamine (1 mg kg(-1)), atropine (1 mg kg(-1)) nor vagotomy inhibited the veratrine-induced pulmonary NO production. These results suggest a role of the sympathoadrenal system in the regulation of pulmonary NO production.

This study compared the effects of high frequency oscillatory ventilation (HFOV) and intermittent mandatory ventilation (IMV) on the homeostasis of nitric oxide (NO) in the lower respiratory tract of healthy rabbits. The mechanisms underlying a putative stretch response of NO formation in the airways were further elucidated. Male New Zealand White rabbits were anaesthetized, tracheotomized and ventilated with IMV or HFOV in random order. Total NO excretion increased from 9.6 +/- 0.8 nl min-1 (mean +/- S.E.M.) during IMV to 22.6 +/- 2.7 nl min-1 during HFOV (P < 0.001). This increase was not explained by changes of functional residual capacity ([Delta]FRC). A similar increase in NO excretion during HFOV was seen in isolated buffer-perfused lungs under constant circulatory conditions (P < 0. 05, n = 4). Intratracheal mean CO2 and NO concentrations, measured at 2.5, 5, 7.5 and 10 cm below tracheostomy, increased significantly with increasing distance into the lung during both IMV and HFOV (P < 0.001 for each comparison). At every intratracheal location of the sampling catheter, particularly low in the airways, both CO2 and NO concentrations were significantly higher during HFOV than during IMV (P < 0.01 for each comparison). We conclude that HFOV increases pulmonary NO production in healthy rabbits. Increased stretch activation of the respiratory system during HFOV is suggested as a possible underlying mechanism. The increase in mean airway NO concentrations may have biological effects in the respiratory tract. Whether it can account for some of the benefits of HFOV treatment needs to be considered.

Bronchial asthma is associated with increased levels of exhaled nitric oxide which are suppressible by glucocorticosteroid inhalation. Children with bronchial asthma were studied to elucidate the relation between endogenous NO release and recent symptoms of bronchial obstruction. Twenty-five children with atopic asthma and 11 healthy control subjects were enrolled and exhaled NO was studied using chemiluminescence analysis. The subjects breathed purified air (

Nitric oxide (NO) is continuously produced in the lung and is present in exhaled air. We examined the effect of β-adrenoceptor stimulation on the production of pulmonary NO in rabbits. Exhaled NO was measured by chemiluminescence in anaesthetized and mechanically ventilated rabbits and in buffer-perfused rabbit lungs. Intravenous infusions of adrenaline (0.1–10 μg kg−1 min−1) elicited dose-dependent increases in exhaled NO. The increases in exhaled NO comprised an initial peak followed by a lower plateau level. The increase in exhaled NO was inhibited by propranolol (1 mg kg−1) but not by phentolamine (1 mg kg−1). Prenalterol, a β1-adrenoceptor agonist, and terbutaline, a β2-adrenoceptor agonist, also caused dose-dependent increases in exhaled NO. However, prenalterol was >100 times more potent than terbutaline. Infusions of forskolin (0.01–0.03 μmol kg−1 min−1), an adenylate cyclase stimulator, elicited dose-dependent decreases in blood pressure and concomitant increases in heart rate but caused no alterations in exhaled NO. Nimodipine, a L-type calcium channel blocker, antagonized the increases in exhaled NO in response to prenalterol infusions. The increases in exhaled NO in response to adrenaline and prenalterol were also present in blood-free, buffer perfused lungs during constant-flow conditions. These results demonstrate that pulmonary nitric oxide production can be enhanced by β-adrenoceptor stimulation. Furthermore, the results indicate that the β-adrenergic stimulation of pulmonary NO production is not critically dependent on cyclic AMP formation but may require intact calcium-channels. British Journal of Pharmacology (1999) 126, 833–839; doi:10.1038/sj.bjp.0702369

Nitric oxide (NO) is detectable in the exhaled gas of adults during spontaneous respiration and, according to current knowledge, mainly originates from the paranasal sinuses. We studied total NO excretion rates by chemiluminescence in preterm infants whose paranasal sinuses are known to be only partially pneumatized. NO excretion was 7.15 +/- 1.13 nl/min (mean +/- SD, range 6.33-9.36 nl/min) measured from spontaneously exhaled nasal gas (n = 6) and 0.3 +/- 0.05 nl/min (range 0.26-0.36 nl/min) measured from the lower airways in intubated individuals (n = 3). These values are considerably lower than those reported for older children and adults. Body weight-related amounts of NO excretion, however, seem comparable between infants and adults.

Pigeon breeder's disease is a common form of hypersensitivity pneumonitis, which is rarely diagnosed in children. We report a seven year old boy, who developed cough, easy fatigue, anorexia and weight loss over a period of two months after having contact with pigeons. The findings on physical examination were tachypnoea and reduced thoracic movements. Chest radiograph showed widespread fine nodular shadowing in both lung fields. Pulmonary function tests demonstrated a restrictive defect and an impaired diffusion. Lymphocytes were highly increased in bronchoalveolar lavage (BAL) fluid. Precipitating antibodies against pigeon excreta was found in the serum. Environmental control of pigeon protein and a course of systemic corticosteroids over 4 months resulted in clinical and lung function improvement. However clinical recovery stopped over several months after discontinuation of steroid therapy. Therefore steroid therapy was reinstalled and continued until complete clinical recovery and pulmonary function occurred, that was 20 months after onset of the disease. Essential for the patient was to avoid further contact with birds. However a prolonged steroid therapy was necessary to achieve complete resolution. Lung function tests were useful for follow up and decisions on further treatment.

Whether and when to transfuse in anemia of prematurity is highly controversial. Some authors suggest transfusions simply if the hemoglobin (Hb) level is below a defined normal range. Others propose the use of clinical or laboratory parameters in anemic patients to decide whether to transfuse or not.A decreasing amount of circulating Hb should cause a compensatory increase in cardiac output (CO) and an increase in arterial serum lactate.In 56 anemic preterm infants (not in respiratory or hemodynamic failure) we analyzed CO after the first week of life using a Doppler sonographic method. At the same time serum lactate levels, Hb levels and oxygen saturation were registered. Nineteen of these patients were given transfusion when they demonstrated clinical signs of anemia by tachycardia180/min, tachypnea, retractions, apneas and centralization (group 2). The remaining 37 patients were not transfused (group 1). Serum lactate, CO, heart rate (HR), oxygen delivery, respiratory rate, capillary refill and Hb were analyzed in both groups and in group 2 before and 12-24 h after transfusion. Data between groups 1 and 2 and in group 2 before and after transfusion were compared.In the 56 patients studied no linear correlation between Hb and CO or between Hb and serum lactate was found. Nor could any correlation be demonstrated between the other variables studied. Examining the subgroups separately, a negative linear correlation was demonstrated between serum lactate and oxygen delivery in group 2. No other significant correlations were detected. However, when the pre- and post-transfusion data were compared in group 2 (increase of Hb from 9.45 (SD 3.44) to 12.5 (SD 3.8) g/100 ml), the CO decreased from 281.3 (SD 162.6) to 224 (SD 95.7) ml/kg per min (p0.01) and serum lactate decreased significantly from 3.23 mmol/l (SD 2.07) before to 1.71 (SD 0.83) after transfusion. Oxygen delivery was 35.8 (+/- 0.19) ml/kg per min group 1, 27.8 (+/- 0.05) pre- and 43.4 (+/- 0.07) post-transfusion in group 2 (p0.01).CO measurements and serum lactate levels add little information to the decision-making process for blood transfusions, as neither CO nor serum lactate levels correlate with HB levels in an otherwise asymptomatic population of preterm infants. In infants where the indication for blood transfusion is made based on traditionally accepted clinical criteria, serum lactate is an additional laboratory indicator of impaired oxygenation, as it correlates significantly with oxygen delivery. A significant lower oxygen delivery in patients in whom blood transfusion is indicated and an increase in oxygen induced by transfusion demonstrate the value of these criteria in identifying preterm infants who benefit from transfusion.

The use of exogenous surfactant and nitric oxide in neonates has reduced the number of infants requiring ECMO. The purpose of this study was to demonstrate whether these two therapeutic options might reduce the number of over 28 days old children with severe ARDS requiring ECMO, without reducing changes of survival and morbidity. Over a 30 month period all non-neonatal ARDS patients transferred to our institution for ECMO evaluation were treated based on a study-algorithm. If they did not fulfill “fast entry criteria” (paO2< 40 for more than 3 hrs.) we first tried different ventilation, vasodilatation, and hemodynamic strategies for max. 4 hrs. (inv. I/E ratio, HFOV, epoprostenol, high doses norepinephrine. If the 01 did not decrease by< 10, 30-280 mg natural surfactant or 1-20 ppm nitric oxide were treatment options depending on the degree of pulmonary hypertension measured by echocardiography and by mixed venous saturation measurements. It was possible to use NO and surfactant sequentially. The patients had different etiologies of ARDS as near drowning, pneumonia, immunosuppression, and sepsis. If their 01 did not decrease by 10 in 8 hrs. ECMO was installed. Nineteen patients were evaluated, 6 improved with conventional therapy, their 01 decreased without a relapse (mean 01 at begin of the study: 38). Six patients improved with surfactant therapy alone (mean 01: 54), 4 patients improved after surfactant and sequential NO-treatment, 3 patients were initially treated with NO, 1 sequentially with surfactant. One patient did not show any benefit from NO or surfactant and was put on ECMO. Three patients died (withdrawal of life support because of severe brain damage caused by the underlying disease). We could not observe any respiratory related failure. No patient had to be discharged on oxygen. A sophisticated treatment algorithm integrating different modern ARDS treatment options can reduce the number of patients requiring ECMO. We speculate however that these options can only be used effectively in centers involved in ARDS treatment quite frequently and that these centers have to provide ECMO as one of their therapeutic tools.

It has been suggested that the delta F508 deletion, the most common mutation in the cystic fibrosis (CF) gene, might be linked to chronic bronchial hypersecretion. We investigated whether such an association could be found in chronic bronchitis, since chronic bronchial hypersecretion is an important and specific element of chronic bronchitis. We screened 100 patients hospitalized for chronic bronchitis with six of the most frequently occurring CF gene mutations: delta F508, R553X, G542X, G551D, N1303K, and 621-1G--T. Only one patient affected by chronic bronchitis and diffuse bronchiectasis was heterozygous for the deletion delta F508; no other mutations were found. This is not significantly different from the expected frequency of CF carriers in northern Europe, which is 1 in 25. Thus, no association between the most commonly occurring cystic fibrosis genes and chronic bronchitis is likely to exist and routine screening of patients without further signs of cystic fibrosis would seem to be of no benefit in northern Europe.

Eine symptomatische bronchopulmonale Beteiligung als extraintestinale Manifestation bei Morbus Crohn ist selten. Wir berichten uber eine 16jahrige Patientin, die 18 Monate nach Beginn einer chronisch entzundlichen Darmerkrankung an einer protrahiert verlaufenden afebrilen Laryngotracheobronchitis mit Gewichtsverlust erkrankte. Zu diesem Zeitpunkt bestanden unter einer Sulfasalazindauertherapie keine intestinalen Symptome. Neben einer leichten restriktiven Ventilationsstorung fand sich radiologisch eine beidseitige interstitielle Zeichnungsvermehrung. Eine Bronchoskopie ergab den Befund einer subglottischen Laryngitis und einer granulomatosen, nicht eitrigen Bronchitis. Histologisch liesen sich in der Bronchialschleimhaut submukos liegende, nicht verkasende epitheloidzellige Granulome nachweisen. Wahrend die Lungenfunktionsveranderungen noch uber Monate persistierten, bildete sich die klinische Symptomatik innerhalb weniger Wochen spontan zuruck. Diskussion: Die Kasuistik soll darauf hinweisen, das eine symptomatische Manifestation des Morbus Crohn am Respirationstrakt auch wahrend einer intestinalen Remissionsphase moglich ist. Differentialdiagnostisch sollte bei Patienten mit Morbus Crohn, die an einer atiologisch ungeklarten Atemwegsymptomatik erkranken, an diese Moglichkeit einer extraintestinalen Beteiligung gedacht werden.

Measurement of leukotriene E4 (LTE4) in urine is a noninvasive method for assessing changes in the rate of total body cysteinyl leukotriene production. Eosinophil protein X (EPX) has been used to assess eosinophil activity and monitor inflammation in bronchial asthma. The aim of the study was to look for differences in urinary LTE4 and EPX concentrations between children with stable atopic asthma and healthy controls and to compare asthmatic children with different disease severity. In addition the relationship was evaluated between urinary LTE4 and EPX levels and lung function. LTE4 was also measured (enzyme immunoassay) together with EPX (radioimmunoassay) in urine and lung function tests were carried out in children with mild asthma (steroid-naive) (n=49), moderate to severe asthma (using inhaled steroids) (n=31) and healthy control subjects (n=28). Urinary leukotriene E4 (LTE4) was significantly higher in children with asthma than in controls (median [25-75 percentile] 238.5 (126.5-375.7) SD 191.8 versus 189 (51-253.2) SD 131.7 pg.mg(-1) creatinine; p=0.021). Urinary EPX was also significantly increased in asthmatic children compared with controls (85.5 [64-131.5] SD 76.2 versus 48.5 [43.2-90] 112.1 microg x mmol(-1) creatinine; p=0.006). There were no differences in urinary LTE4 and EPX between the group of mild and the group of moderate to severe asthmatic children. There were significant associations between the urinary LTE4 and intrathoracic gas volume (ITGV), residual volume (RV), forced expiratory volume in one second (FEV1), forced expiratory capacity (FVC) and maximum expiratory flow rate at 25% of vital capacity (MEF25). Urinary EPX was only correlated with maximum expiratory flow rate at 75% of vital capacity (MEF75). Thus measurement of urinary LTE4 may predict the degree of airflow obstruction in asthmatic children. Urinary LTE4 and EPX are useful markers of airway inflammation and can be helpful in guiding asthma management. There was no correlation between LTE4 and EPX levels.

Endogenous synthesis of nitric oxide (NO) and its presence in exhaled air was observed in various species including humans. Particularly high levels were found in adults with bronchial asthma, possibly because of the underlying pulmonary inflammatory activity. We studied oral and nasal exhaled NO by chemiluminescence in 47 children aged between 6 and 10 years. Thirty children had bronchial asthma, 17 were healthy controls. In asthmatic children oral exhaled NO was 13.4 +/- 1.4 parts per billion (ppb) (mean +/- SEM), nasal exhaled NO was 21.7 +/- 1.5 ppb. In healthy controls oral exhaled NO was 7.2 +/0 1.0 ppb, nasal exhaled NO was 18.2 +/- 22 ppb. Oral exhaled NO was significantly higher in asthmatic children compared to healthy controls (P = 0.0017). Nasal exhaled NO did not differ significantly in the two groups. There was a significant negative correlation between oral exhaled NO and forced expiratory volume in 1 s (FeV1). No significant correlation between oral or nasal exhaled NO and other markers of obstructive lung function impairment, oral minute ventilation, the body mass index and the presence of upper respiratory tract infection could be found.Children with bronchial asthma have significantly higher levels of orally exhaled nitric oxide than healthy controls.

The frequency of six common mutations in the cystic fibrosis transmembrane conductance regulator gene was studied in 100 patients hospitalized with chronic bronchitis. Only one patient with chronic bronchitis and diffuse bronchiectasis was heterozygous for the common delta F508 mutation. R553X, G542X, G551D, N1303K and 621 + 1G-->T were not detected. This result is not significantly different from the frequency of cystic fibrosis carriers in Northern Europe. Predisposition of heterozygotes for chronic bronchitis is therefore unlikely.

Experience with the use of cytotoxic drugs in the first trimester of pregnancy is limited. We report on the clinical phenotype and infantile development of a girl born to a 36-year-old mother. Before recognition of pregnancy, the latter had been treated for acute myelocytic leukaemia receiving cytarabine, daunorubicin and doxorubicin at conception and cytarabine and thioguanine at about 35-37 days post conception. At delivery, there were severe brachycephaly, hypoplasia of the anterior cranial base and the midface as well as synostoses of both coronal and metopic sutures. Further findings included bilateral four-finger hands with hypoplastic thumbs and absent radii. This phenotype is reminiscent of the Baller-Gerold syndrome. The child, at present 15 months old, has had to undergo two operations for fronto-orbital advancement because of insufficient growth of the mid-face, nasal airway hypoplasia and increased intracranial pressure. Motor milestones are slightly retarded--neurodevelopment is otherwise normal. These findings are discussed in the context of the few previous reports and are particularly important for future genetic counselling.

We report a 10-month-old male infant who was admitted to our hospital with a history of failure to thrive and bulky stools. On examination, he was dystrophic and had a protruding abdomen, but he was well oxygenated and his lungs were clear on auscultation. A tachycardia of 145 beats per min and radiological evidence of cardiomegaly indicated involvement of the heart, but an ECG failed to show signs of myocarditis or cardiac hypertrophy. An elevated sweat chloride concentration of 141 mEq/l confirmed the diagnosis of cystic fibrosis (CF). Molecular analysis revealed heterozygosity for the common mutation delta F508. He died unexpectedly of a sudden cardiac arrest 2 days later. Autopsy revealed scattered myocardial necrosis and fibrosis. Some 50 documented cases of myocardial fibrosis in infants with CF have been reported. Suggested causes such as malnourishment and hypovitaminosis remain speculative as systematic studies have yet to be done.

It has been shown recently that autosomal dominant retinitis pigmentosa may be caused by point mutations of the rhodopsin gene in a portion of families. In this communication, a large six-generation family with autosomal dominant RP is described. Molecular analysis by PCR amplification followed by restriction digestion or heteroduplex analysis suggested a point mutation in codon 347, in which two different mutations (Pro-347-Ser and Pro-347-Leu) have already been reported. Direct sequencing of the patients' DNA revealed a previously undescribed CCG → CGG transversion in codon 347 predicting a Pro → Arg substitution. Ophthalmological data of the patients are summarized and compared to those of patients with other mutations in the rhodopsin gene.

Seventy-seven cases of meningioma (15 with single or multiple recurrences), selected on the basis of their histologic subtypes, and nine cases of neurilemoma were analyzed immunohistochemically for the presence of the five classes of intermediate filament proteins, neuron-specific enolase (NSE), protein S-100, epithelial membrane antigen (EMA), and HNK-1 (Leu-7). Most antibodies were studied with the alkaline phosphatase-antialkaline phosphatase method. The peroxidase-anti-peroxidase and avidin-biotin-complex methods were used for Leu-7 and NSE, respectively. Meningiomas were subdivided into groups showing cytokeratin or protein S-100 positivity. Coexpression of these two markers was rare (5%) and occurred in meningotheliomatous meningiomas only. Only in these cases was cytokeratin expression more frequent than in meningiomas taken together (33% versus 20%). In contrast, protein S-100 expression was less frequent (46% versus 60% on average). In fibrous meningiomas, both cytokeratins and NSE were expressed less frequently than on average (11% versus 20%, 67% versus 88%, respectively). Protein S-100 occurred in a higher percentage of cases. Transitional meningiomas did not show cytokeratin expression. Protein S-100 occurred in a higher percentage of cases. Transitional meningiomas did not show cytokeratin expression. Protein S-100 was expressed slightly more often than in the other subtypes. Psammomatous meningiomas coexpressed more markers than any other subtype. Hemangioblastic and hemangiopericytic forms did not stain for EMA, but otherwise showed a staining profile similar to that of meningiomas. HNK-1 was expressed in 29% of meningiomas, particularly among tumors with anaplastic histologic features. There was no marker that retrospectively indicated impending recurrences.

We present a case of a giant mullerian duct cyst with components of clear cell adenocarcinoma in a 15-year-old boy. Complete tumor resection was achieved in two steps. The presented case with a combination that has never been described before may change the perspective of treatment approaches for this rare entity.

Acute lymphoblastic leukaemia (ALL) was diagnosed in a 36-year-old and treated with cytarabin, daunorubicin, doxorubicin and cytarabin, thioguanin, respectively, in an unrecognized pregnancy at conception and at about 35-37 days p.c., Amniocentesis at 16 weeks of gestation revealed a normal female karyotype. At delivery, brachycephaly, hypoplasia of supraorbital bony structures and hypotelorism were seen. Hypoplastic nasal root, bilateral choanal atresia and micrognathia caused hypoplasia of naso- and oropharynx. There was also bilateral aplasia of the radius and hypoplasia of the first ray of the hands. Internally, an atrial septal defect II could be demonstrated. The malformations detected are in accord with the timing of teratogenesis. Neurodevelopment is normal at the age of 8 months. Experience with the use of cytotoxic drugs in pregnancy has so far been limited to folate antagonists.