Clinical spectral characterisation of colonic mucosal lesions using autofluorescence and delta aminolevulinic acid sensitisation.

BACKGROUND AND AIMS: Laser induced fluorescence (LIF) from colonic mucosa was measured in vivo with and without delta aminolevulinic acid (ALA) in an attempt to differentiate between neoplasia and non-neoplasia in real time during colonoscopy. METHODS: Spectra from 32 adenomas, 68 normal sites, and 14 hyperplastic polyps in 41 patients were obtained with a point monitoring system. Twenty one of the patients had been given a low dose of ALA as a photosensitiser before the examination. Light of 337, 405, or 436 nm wavelength was used as excitation. Stepwise multivariate linear regression analysis was performed. RESULTS: With 337 nm excitation, 100% sensitivity and 96% specificity was obtained between normal mucosa and adenomas. Seventy seven per cent of the hyperplastic polyps were classified as non-neoplastic. When exciting with 405 and 436 nm, the possibility of distinguishing different types of tissue was considerably better in the ALA patients than in the non-ALA patients. CONCLUSIONS: The in vivo point measurements imply that a good discrimination between normal tissue and adenomatous polyps can be obtained using the LIF technique. Excitation at 337 nm and at 405 nm or 436 nm using ALA gives good results. LIF also shows potential for distinguishing adenomatous from hyperplastic polyps. The number of detection wavelengths could be reduced if chosen properly.

Fluorescence diagnostics and kinetic studies in the head and neck region utilizing low-dose delta-aminolevulinic acid sensitization.

Diagnostic measurements and pharmacokinetic studies were performed in 17 patients with various kinds of malignant, premalignant and benign lesions in the head and neck region by means of point monitoring laser-induced fluorescence. For marking different types of tissue, delta-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) was used. The ALA-induced PpIX synthesis was monitored at different time intervals after oral administration of ALA in low doses, 5 and 15 mg/kg b.w. Besides the porphyrin-related signal the tissue endogenous fluorescence was also recorded. The fluorescence spectra were evaluated at two different wavelengths corresponding to the specific drug-related fluorescence peak and the endogenous tissue fluorescence emission at 635 and 490 nm, respectively. The evaluated fluorescence data were correlated to the histopathological tissue investigation. A fall-off in the overall fluorescence intensity at 490 nm was obtained for all the malignant and premalignant areas, as well as an increased red fluorescence. A ratio between the red and the blue/green fluorescence intensity was formed for each time interval after the ALA administration. The lower drug dose seems to be sufficient to obtain a useful demarcation ratio between normal and diseased tissue with a very low PpIX fluorescence intensity in the normal tissue. A PpIX fluorescence maximum seems to occur between 3 and 4 h in normal tissues, whereas malignant tumour tissue shows a higher level for a longer period of time.

Clinical multi-colour fluorescence imaging of malignant tumours--initial experience.

PURPOSE: The detection of malignant tumours relies on a variety of diagnostic procedures including X-ray images and, for hollow organs, endoscopy. The purpose of this study was to present a new technique for non-invasive tumour detection based on tissue fluorescence imaging. MATERIAL AND METHODS: A clinically adapted multi-colour fluorescence system was employed in the real-time imaging of malignant tumours of the skin, breast, head and neck region, and urinary bladder. Tumour detection was based on the contrast displayed in fluorescence between normal and malignant tissue, related to the selective uptake of tumour-marking agents, such as haematoporphyrin derivative (HPD) and delta-amino levulinic acid (ALA), and natural chromophore differences between various tissues. In order to demarcate basal cell carcinomas of the skin, ALA was applied topically 4-6 h before the fluorescence investigation. For urinary bladder tumour visualisation (transitional cell carcinoma of different stages including carcinoma in situ), ALA was instilled into the bladder 1-2 h prior to the study. Malignant and premalignant lesions in the head and neck region were imaged after i.v. injection of HPD (Photofrin). Finally, the extent of in situ and invasive carcinomas of the breast was investigated in surgically excised specimens from patients that received a low-dose injection of HPD 24 h prior to the study. The tumour imaging system was coupled to an endoscope. Fluorescence light emission from the tissue surface was induced with 100-ns-long optical pulses at 390 nm, generated from a frequency-doubled alexandrite laser. With the use of special image-splitting optics, the tumour fluorescence, intensified in a micro-channel plate, was imaged in 3 selected wavelength bands. These 3 images were processed together to form a new optimised-contrast image of the tumour. This image, updated at a rate of about 3 frames/s, was mixed with a normal colour video image of the tissue. RESULTS: A clear demarcation from normal surrounding tissue was found during in vivo measurements of superficial bladder carcinoma, basal cell carcinoma of the skin, and leukoplakia with dysplasia of the lip, and in in vitro investigations of resected breast cancer. CONCLUSIONS: The initial clinical experience of using multi-colour fluorescence imaging has shown that the technique has the potential to reveal malignant tumour tissue, including non-invasive early carcinoma and also precancerous tissue. Further investigations are needed to fully develop the method.

External cephalic version at term with tocolysis and vibroacoustic stimulation.

OBJECTIVE: This study compared the obstetric outcome in women who had external cephalic version (ECV) for breech presentation after 36 weeks gestation with those who did not, to see whether ECV reduces breech deliveries and cesarean section rates with reduced complications. METHOD: External cephalic version was attempted in 200 women (study group) with the use of tocolysis and vibroacoustic stimulation. The control group (ECV not attempted) comprised of 278 women with breech presentation after 36 weeks. RESULT: The cesarean section rate was 14.0% in the successful version group compared with 55.2% in the unsuccessful version group. The overall cesarean section rate in the study group was 32.5%. In the control group of 278, the fetus remained in the breech presentation in labor in 269 women with a cesarean section rate of 51.4% which was not different from the unsuccessful version group (55.2%). CONCLUSION: This study supports the randomized trials conducted earlier in that ECV after 36 weeks gestation reduced the number of breech deliveries and cesarean sections (32.5% in the study group compared with 51.4% in the control group) (P > 0.00001).

Medical prevention of pre-eclampsia.

There is no clear evidence that any of the antihypertensive drugs available can defer or prevent the occurrence of proteinuric pre-eclampsia or associated problems such as fetal growth retardation or perinatal death. When antihypertensive treatment is indicated, there seems to be no reason to prefer any of the tested beta-blockers, or to prefer labetalol to a pure beta-blocker, or indeed, to prefer beta-blockers to methyldopa. The increased maternal, fetal and infant mortality and morbidity associated with hypertension in pregnancy justify careful evaluation of the risks of the more severe forms of hypertension at an early stage in all pregnancies. A careful family and medical history are benchmarks in pregnancy surveillance, followed by meticulous monitoring of the pregnant mother in a well organized maternity health care system where high maternal compliance is necessary together with use of appropriate methods to predict hypertension early. Prophylactic treatment with medication causing least harm to the mother and fetus to prevent serious complication due to hypertension in pregnancy when increased risk is identified would be of value and further improve maternal and fetal outcome.

Fetal and neonatal haemodilution associated with multiple placental chorioangioma: case report.

A pregnancy with polyhydramnios and abnormal antepartum fetal heart rate pattern was found to have multiple placental haemangiomas. Multiple placental haemangiomas can give rise to fetal cardiac failure due to a hyperdynamic circulation or fetal anaemia either due to haemodilution or possibly destruction of blood cells in the chorioangioma. Whether fluid restriction with or without diuretics or blood transfusion is the correct form of treatment of neonatal cardiac failure in such a case is discussed.

Randomised controlled trial of methyldopa and isradipine in preeclampsia--effects on uteroplacental and fetal hemodynamics.

This is a prospective randomised controlled study in 21 women admitted with preeclampsia in the third trimester. The mean arterial blood pressure decreased by 11.1 mmHg (95% confidence interval -14.9 to -7.3 mmHg) in the methyldopa group, and by 9.3 mmHG (95% confidence interval-14.4 to -4.2 mmHG) in the isradipine group. The maternal heart rate decreased by 6.9 beats per min (95% confidence interval -11.6 to -2.2 bpm) during methyldopa treatment, and by 2.5 beats per min (95% confidence interval -9.2 to 4.3) during isradipine treatment. Pulsatility index in maternal and fetal vessels was not affected by either of the two drugs. The birth weight and placental weight and neonatal outcome were similar and uneventful. The hypotensive effect was similar for methyldopa and isradipine. Except reduced maternal heart rate on methyldopa, fetal and uteroplacental hemodynamics were not altered during treatment of preeclampsia with methyldopa or isradipine.

Automated 24-hour ambulatory blood pressure monitoring in preeclampsia.

A prospective controlled study was designed to compare automated 24-hour ambulatory blood pressure monitoring with intermittent blood pressure recordings obtained using a sphymomanometer. Blood pressure was measured in 20 hospitalized preeclamptic women in the third trimester. Data obtained using the Spacelabs automated blood pressure monitor was recorded over a period of 24 hours, and thereafter stored and processed in a computer. During the same 24 hour period, blood pressure and heart rate were measured by experienced staff at 07.00, 10.00, 13.00, 15.00, 18.00 and 21.00 hours, with the patient in a semi-recumbent position using a conventional mercury sphygmomanometer with a cuff of appropriate size. Korotkoff phase 5 was used as the indicator of diastolic blood pressure in all recordings by the staff. The main outcome measures were systolic and diastolic blood pressure, mean arterial blood pressure and maternal heart rate. Automated ambulatory monitoring was well tolerated and gave 91.6% successful readings. The mean differences between the blood pressure readings recorded by the monitor and of intermittent mercury sphygmomanometry during daytime were 0.7 (95% confidence interval -2.6 to 4.0) mmHg for the mean arterial blood pressure, -1.7 (95% confidence interval -6.8 to 3.5) mmHg for the systolic blood pressure, and 1.9 (95% confidence interval -2.2 to 6.0) mmHg for the diastolic blood pressure. The mean differences between day-time and night-time monitored blood pressures were 4.3 (95% confidence interval 0.8 to 7.8) mmHg, 4.6 (95% confidence interval 2.0 to 7.2) mmHg, and 4.4 (95% confidence interval 1.5 to 7.2) mmHg, respectively. The number of patients diagnosed as being hypertensive was similar whether automated blood pressure monitor or mercury sphymomanometry was used. Mean maternal heart rate recorded by the monitor or by the staff did not differ. Automated ambulatory blood pressure monitoring is reliable and might improve our understanding of the dynamic changes in blood pressure in pre-eclamptic women and may be a more suitable method to assess the blood pressure control achieved by different drugs.

Maternal mortality: evolving trends.

Despite improvement in socioeconomic standards, good and accessible health care facilities the maternal mortality rate in Singapore is not declining. The maternal mortality rate in National University Hospital, Singapore, over a 7 year period 1986-1992 was 22.9 per 100,000 when direct and indirect causes were considered (34.4 per 100,000 when incidental deaths were included). However closer scrutiny reveals that most deaths were not due to the traditional direct causes of haemorrhage, sepsis, embolism or hypertensive disease. Most were due to medical disorders which in their own right carries a high risk to life even without a pregnancy.

PIP: Obstetrician-gynecologists reviewed patient records of women delivering during January 1986-December 1992 to determine the maternal mortality rate and trends and the causes of maternal deaths in the maternity ward at the National University of Singapore. There were 26,173 deliveries and 9 maternal deaths (a maternal mortality rate of 22.9/100,000). The causes of maternal deaths were pulmonary embolism (underlying condition, systemic lupus erythematosus [SLE]), hemorrhage from multiple sites (thrombotic thrombocytopenia), acute exacerbation of SLE with interstitial pneumonitis, pulmonary fibrosis (systemic sclerosis), fulminant hepatitis (prior hepatitis and liver disease), and cerebral embolism (rheumatic heart disease with mitral valve replacement). There were also three incidental maternal deaths bringing the maternal mortality rate up to 34.4/1000. The incidental causes of death included septicemia from perforated peptic ulcer (uncontrolled thyrotoxicosis), multiple metastases from lung cancer, and suicide (family dispute over adoption of newborn). A cesarean section preceded 4 (44%) of the 9 maternal deaths. Two of these deaths were incidental maternal deaths. Cesarean section was related to two of the remaining six (33%) deaths. These findings show that traditional direct causes of maternal death (hemorrhage, sepsis, embolism, or hypertension) were not responsible for the maternal deaths at this tertiary facility. Instead, the women tended to have medical conditions that placed them at high risk of death regardless of pregnancy status.

Evaluation of a simple method to assess fetal well-being in antenatal clinic.

To study the feasibility of assessing fetal heart rate (FHR) acceleration by a fetal doptone and fetal movements (FM) as perceived by the mother and observed by the attendant in response to a vibroacoustic stimulus. Baseline FHR and it's response during the first minute after vibroacoustic stimulation was observed by a fetal doptone with a digital display on 317 occasions in 201 pregnancies (81.4% of whom were high risk) during antenatal visits in the third trimester. Fetal movements in response to the stimulus were recorded by the mother and the examiner. FHR increased 15 beats greater than the baseline rate for > 15 secs in 269 of the tests (83.4%), and fetal movements were observed by the mother in 301 (94.9%) of the tests. A FHR increase in > or = 15 bpm together with maternal and examiner perceived fetal movements were observed in 250 tests (81.7%). Good correlation was seen between the mother and the examiner (97.8%) of the observation of presence or absence of fetal movements to the vibroacoustic stimulus. One of the three parameters i.e. increase in FHR > or = 15 beats > or = 15 secs or perception of fetal movement either by the mother or the observer were present in 98.1% of the tests. If it could be considered that one of these three signs are indicative of good fetal health further investigations of fetal well-being would be needed in only 1.9%. The fetal outcome was uneventful in all pregnancies studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of methyldopa and isradipine on fetal heart rate pattern assessed by computerized cardiotocography in human pregnancy.

OBJECTIVE: The effects of two antihypertensive drugs, methyldopa and isradipine, on fetal heart rate pattern were analyzed by computerized cardiotocography. STUDY DESIGN: The first part of the study was a prospective, randomized, controlled trial of 19 women with preeclampsia in the third trimester given 2.5 mg of oral slow-release isradipine twice a day or 250 mg of methyldopa three times a day. In a second part of the study 23 women with preeclampsia in the third trimester given 5 mg of oral slow-release isradipine twice a day were compared with 23 matched controls without medication. Main outcome measures were maternal blood pressure and mean baseline fetal heart rate, fetal movements, number of accelerations, periods of high and low baseline variability, and mean baseline heart rate variability. RESULTS: Compared with the pretreatment value, the mean arterial blood pressure decreased significantly in all drug treatment groups. Fetal heart rate characteristics were not significantly changed during drug treatment or bed rest. CONCLUSION: The various features of the fetal heart rate pattern evaluated by computerized methods were not influenced by treatment with methyldopa or isradipine.

Need for fetal assessment prior to and during external cephalic version. Occurrence of transient cardiac asystole.

We encountered two cases of cardiac asystole for one and three minutes respectively following external cephalic version. We describe the two cases and discuss the necessity for one to be aware of such an event and the possible advantage of performing a fetal heart rate (FHR) recording prior to the procedure and observation of the FHR during the version.

Plasminogen activators, plasminogen activator inhibitors and markers of intravascular coagulation in pre-eclampsia.

In pre-eclampsia (PE), reduced levels of plasma urokinase-like plasminogen activator (u-PA) and plasminogen activator inhibitor-2 (PAI-2), and increased levels of plasma tissue-type plasminogen activator (t-PA) antigen were seen. The majority of moderate and severe pre-eclamptic women (7 out of 10) ended up with pre-term delivery as compared with 2 out of 11 who went on to term. Patients with moderate and severe PE had significantly lower levels (mean +/- SD, ng/ml) of PAI-2 (58.4 +/- 34.9) and u-PA antigen (1.61 +/- 0.62) as compared to those with mild PE (95.6 +/- 39.3 and 1.61 +/- 0.62 and 2.12 +/- 0.61, respectively). Significantly raised t-PA antigen (14.6 +/- 5.7 ng/ml) was seen in moderate and severe PE as compared with mild PE (9.9 +/- 3.4 ng/ml). PAI-1 activity was significantly raised only in moderate and severe PE as compared with normal pregnancy. There were no significant differences in thrombin-antithrombin-III complexes, D-dimer and beta-thromboglobulin levels between the PE group and normal pregnancy, although these parameters were above the non-pregnant levels. Platelets in PE were within the range found in normal pregnancy. It appears that measurements of plasma u-PA and PAI-2 levels in patients with PE may have prognostic value in determining the outcome of pregnancy in this pregnancy disorder.

Effects of methyldopa on uteroplacental and fetal hemodynamics in pregnancy-induced hypertension.

OBJECTIVE: Our purpose was to study the effect of methyldopa on uteroplacental and fetal hemodynamics in women with pregnancy-induced hypertension. STUDY DESIGN: A prospective study of Doppler ultrasonographic blood flow data before and after 1 week of methyldopa treatment was conducted at the Department of Obstetrics and Gynecology, National University Hospital, Singapore, in 20 women (mean 35 weeks' gestation) with pregnancy-induced hypertension. The main outcome measures were maternal blood pressure, maternal and fetal heart rate, and blood velocity waveforms characterized by the pulsatility index in the fetal ascending aorta, middle cerebral artery, umbilical artery, and maternal uterine and arcuate arteries. Statistical evaluation was performed with t tests for paired observations. RESULTS: Maternal mean arterial blood pressure was reduced 9.7 mm Hg (95% confidence interval -13.8 to -5.6), and mean heart rate decreased 6.3 beats/min (95% confidence interval -11.1 to -1.4). Mean pulsatility index in the uterine (0.93 to 0.92) and arcuate arteries (0.61 to 0.73) were unchanged after treatment. Fetal hemodynamic changes before and after treatment were not significant. Fetal and neonatal outcome was uneventful. CONCLUSION: Short-term treatment with methyldopa in the last trimester in women with pregnancy-induced hypertension reduced maternal blood pressure and heart rate but had no adverse effects on uteroplacental and fetal hemodynamics.

Randomised controlled trial of atenolol and pindolol in human pregnancy: effects on fetal haemodynamics.

OBJECTIVE: To compare the effects of uteroplacental circulation of two beta adrenoceptor blockers, atenolol (cardioselective) and pindolol (non-selective with intrinsic sympathomimetic activity). DESIGN: Controlled double blind double dummy study. SETTING: Departments of obstetrics and gynaecology in two Swedish university hospitals. SUBJECTS: 29 women with pregnancy induced hypertension in the third trimester, 13 randomised to atenolol and 16 to pindolol. MAIN OUTCOME MEASURES: Pulsatility index in fetal aorta, umbilical artery, and maternal arcuate artery. Volumetric blood flow in fetal aorta and umbilical vein. RESULTS: Mean arterial blood pressure decreased by 9.0 (95% confidence interval -13.0 to -5.0) mm Hg in the atenolol group and by 7.8 (-11.4 to -4.2) mm Hg in the pindolol group. During atenolol treatment the pulsatility index increased significantly from 1.82 (SD 0.20) to 2.07 (0.32) in the fetal thoracic descending aorta, from 1.44 (0.28) to 1.79 (0.27) in the abdominal aorta, and from 0.93 (0.17) to 1.05 (0.19) in the umbilical artery; the volumetric blood flow in the umbilical vein decreased from 106 (28.8) to 84 (22.6) ml/min/kg. No such changes were seen after treatment with pindolol. Birth weight was similar in the two groups but placental weight was significantly different (529 (122) g in atenolol group v 653 (136) g in pindolol group; p = 0.03). CONCLUSION: The hypotensive effect was similar with both drugs, but only the beta 1 blocker atenolol had significant effects on fetal haemodynamics, although within normal ranges. The implications of these findings can be only speculative, but negative fetal consequences of beta 1 adrenoceptor blockade cannot be excluded.

Computerised cardiotocography following vibro-acoustic stimulation.

To study the effect of vibro-acoustic stimulation (VAS) to the mean fetal heart rate (FHR), period of high and low FHR variation, overall variation (msec and bpm) and short term variation (msec). In a prospective study 17 pregnant women between 34-42 weeks gestation admitted to antenatal ward for obstetric complications two 60 min FHR recording was carried out with an interval of 30 min in between recordings. On a random basis the fetus was stimulated by a vibro-acoustic stimulator for 5 sec at the beginning of one of the two 60 min FHR recordings. Automated analysis of the FHR, tocodynamometry, and maternal perception of fetal movements was done by a commercially available computerized programme (System 8000). It was possible to obtain the two 60 min recordings with signal loss of < 10% in 12 out of 17 patients. No changes were observed when the FHR parameters for 60 min after VAS was compared with the control period. When analyzed in segments of 0 to 10, 11 to 20, 20 to 40 and 41 to 60 min the mean baseline FHR was significantly higher after VAS during the first 10 minutes compared with any 10 or 20 min segment of the control period or any such segments 10 min after VAS. Concomitantly the overall variation and short-term variation was significantly lower during the first 10 minutes following VAS (p < 0.05) compared with the parameters in the corresponding periods during the control period.(ABSTRACT TRUNCATED AT 250 WORDS)

Vibro-acoustic stimulation does not alter the duration of high and low fetal heart rate variability episodes.

To study the effect of vibro-acoustic stimulation on high and low fetal heart rate (FHR) variability episodes. Prospective control study, in 21 high risk pregnancies between 32 to 39 weeks gestation. FHR pattern was recorded with cardiotocograph (CTG). After 5 min low FHR variability a vibro-acoustic stimulator was activated in contact with or above the maternal abdomen (sham) on a random basis on two consecutive days, and CTG was continued to obtain a complete high and low FHR variability cycle. Complete high and low FHR variability cycles were obtained in 12 patients with mean recording time of 129.5 minutes (range 69-185 min). The mean baseline FHR increased by 32.5 +/- 9.4 bpm after contact vibro-acoustic stimulation, but remained unchanged after sham stimulation. Mean duration of high FHR variability was 56.6 +/- 32.9 min and 47.3 +/- 23.7 min, respectively, and mean duration of the consecutive low FHR variability episode was similar after contact and sham stimulation. The complete cycles were 71.1 +/- 34.7 min and 66.2 +/- 21.2 min, respectively. Vibro-acoustic stimulation induced an abrupt change from low to high FHR variability, but the complete cycle of high and low FHR variability was not altered, when compared with the corresponding cycle following sham stimulation on the same fetus.

Fetal and infant outcome of pregnancies with very early rupture of membranes.

Fetal and infant outcome was studied in 38 singleton pregnancies complicated by very early rupture of membranes (PROM), in gestational weeks 19-29, over a 4-year period, in a Swedish population. The pregnancies were managed according to a specified protocol, including postponement of delivery until 34 weeks of gestation if possible. Stillbirth occurred in 10 cases (26.3%), all with PROM before 26 completed weeks, while 6 other infants died in the neonatal period. Respiratory distress syndrome was evident in half (50.0%) of the 28 liveborn infants. The surviving 22 infants (57.9%) were followed up to 2 years of age. The rate of neurological sequelae at follow-up was 22.7% (5/22). The fetal outcome of the 20 pregnancies with rupture of membranes before 26 completed weeks was poor; only 7 infants of the 10 born alive survived the neonatal period. The short-term fetal outcome in the group with rupture of membranes in 26-29 completed weeks was better: 15 of the 18 infants survived, but 4 had neurological sequelae. PROM before 29 completed weeks of gestation is associated with severe short-term and long-term fetal complications, in cases where the pregnancy is prolonged for several weeks.