The activity of the von Willebrand factor cleaving protease ADAMTS-13 in newborn infants.

BACKGROUND: Unusually large von Willebrand factor (VWF) multimers have been observed in patients with thrombotic microangiopathies (TMA), and absence of the VWF cleaving protease ADAMTS-13 activity is considered to be involved in the etiology of TMA. Increased amounts of large multimers of VWF have also been identified in neonates. OBJECTIVE: We assessed ADAMTS-13 activity in healthy neonates, children and adults to establish baseline levels. PATIENTS AND METHODS: Cord blood was collected from 38 full-term newborns; venous samples were taken from 15 neonates on day 2-3 of life. Seventeen children, 24 healthy adults and seven patients with TMA were studied as well. ADAMTS-13 activity was quantified by the binding of the subjects' plasma VWF to collagen before and after enzyme activation. The multimer distribution of VWF was also determined. RESULTS: Neonates and children had percentage ADAMTS-13 activity similar to adults. However, two groups were apparent in the cord blood samples: while 28/38 newborns had percentage activity within the normal range of healthy adults (102 +/- 3.0%), 10 had significantly lower percentage activity (53 +/- 1.1%; P < 0.0001) that normalized by day 2-3. The VWF multimer distribution was the same in all cord blood samples and was not different compared with children and adults. High-molecular-weight VWF multimers were significantly increased in the 2-3-day-old neonates and in TMA patients. CONCLUSIONS: Although ADAMTS-13 activity was similar in neonates compared with adults, 26% of neonates had mildly reduced activity. Further studies are needed to investigate the complex interaction of VWF production and secretion with its size control by ADAMTS-13 in different age groups.

Alternative approaches to preterm labor.

Alternative approaches to the management of preterm labor have included home uterine activity monitoring, long-term tocolysis, bed rest, and intravenous hydration. Current evidence in the literature does not support improved pregnancy outcomes with these various therapies.

Multiple courses of antenatal corticosteroids: a systematic review and meta-analysis.

OBJECTIVE: To assess the effects of multiple courses of antenatal corticosteroids on perinatal and neonatal death and neonatal, infant, and maternal disease. METHODS: MEDLINE and Embase were searched for human studies published in English. Studies that compared multiple courses of antenatal corticosteroids versus a single course were included if they were published in full and were controlled for gestational age at birth. Meta-analyses (odds ratio and 95% confidence interval) were undertaken when possible. RESULTS: Eight observational studies were included. Selection bias was present in all studies. Multiple courses of antenatal corticosteroids were associated with a decreased risk of respiratory distress syndrome (odds ratio, 0.79; 95% confidence interval, 0.64 to 0.98) and patent ductus arteriosus (odds ratio, 0.56; 95% confidence interval, 0.35 to 0.90) and were associated with an increased risk of endometritis (odds ratio, 3.42; 95% confidence interval, 1.92 to 6.11). There was no significant effect on other neonatal and maternal outcomes. CONCLUSION: It is not possible to establish the true effects of multiple courses of antenatal corticosteroids by a review of the results of observational studies because of the effect of confounding variables. Randomized controlled trials are needed to address this important issue.

Prospective multicenter study of pregnancy outcomes in women with heart disease.

BACKGROUND: The maternal and neonatal risks associated with pregnancy in women with heart disease receiving comprehensive prenatal care have not been well defined. METHODS AND RESULTS: We prospectively enrolled 562 consecutive pregnant women with heart disease and determined the outcomes of 599 pregnancies not ending in miscarriage. Pulmonary edema, arrhythmia, stroke, or cardiac death complicated 13% of pregnancies. Prior cardiac events or arrhythmia, poor functional class or cyanosis, left heart obstruction, and left ventricular systolic dysfunction independently predicted maternal cardiac complications; the cardiac event rate can be predicted using a risk index incorporating these predictors. Neonatal complications (20% of pregnancies) were associated with poor functional class or cyanosis, left heart obstruction, anticoagulation, smoking, and multiple gestations. CONCLUSIONS: Pregnancy in women with heart disease is associated with significant cardiac and neonatal complications, despite state-of-the-art obstetric and cardiac care. Maternal cardiac risk can be predicted with the use of a risk index.

Fetal response to maternally administered morphine.

OBJECTIVE: We sought to determine the effects of maternally administered morphine on fetal response. STUDY DESIGN: Singleton pregnancies requiring fetal blood sampling were enrolled. Only study patients were given morphine intramuscularly. Maternal vital signs, fetal heart rate, biophysical profile score, and umbilical artery Doppler indices (systolic/diastolic ratio, resistance index, and pulsatility index) were completed before and after fetal blood sampling. Maternal and cord blood morphine concentrations were measured. RESULTS: Ten study and 6 control patients were enrolled. A significantly lower biophysical profile score was observed in study patients (P =.001) as a result of absent fetal breathing movements and nonreactive nonstress tests. Gross and fine fetal movements were unaffected. A significant correlation was measured between the biophase morphine concentration and each of the Doppler indices. CONCLUSION: Morphine administered to the mother causes a significant decrease in the biophysical profile score. Correlation between the biophase morphine concentration and the Doppler indices was calculated. These results suggest that morphine acts as a vasoconstrictor of the placental vasculature but do not support the use of intramuscular morphine to suppress fetal movement.

Prediction of perinatal outcome in fetuses suspected to have intrauterine growth restriction: Doppler US study of fetal cerebral, renal, and umbilical arteries.

PURPOSE: To determine and compare the diagnostic performance of fetal middle cerebral (MCA), renal (RA), and umbilical (UA) arterial Doppler ultrasonography (US) for prediction of adverse perinatal outcome in suspected intrauterine growth restriction (IUGR). MATERIALS AND METHODS: Two hundred ninety-three small-for-gestational age fetuses (24-39 weeks at recruitment and US-estimated weight or abdominal circumference below 10th percentile) were prospectively examined with Doppler US of the UA, MCA, and RA. Clinicians were blinded to MCA and RA Doppler measurements. RESULTS: Seventy-six fetuses (25.9%) had at least one major or minor adverse perinatal outcome. Major outcomes included stillbirth, neonatal death, neurologic complication, and necrotizing enterocolitis. The MCA pulsatility index (PI), compared with the UA PI and RA PI, was more sensitive (72.4% vs 44.7% and 8.3%) but less specific (58.1% vs 86.6% and 92.6%) in predicting adverse outcome. The UA PI had the highest positive likelihood ratio (ratio, 3.3); the MCA PI had the lowest negative likelihood ratio (ratio, 0.48). When gestational age at the first Doppler US examination was less than 32 weeks, the MCA PI had a sensitivity of 95.5% and negative predictive value of 97.7% for major adverse outcome (negative likelihood ratio, 0.10). CONCLUSION: In suspected IUGR, while an abnormal UA PI is a better predictor of adverse perinatal outcome than an abnormal MCA or RA PI, a normal MCA PI may help to identify fetuses without major adverse perinatal outcome, especially before 32 weeks gestational age.

The effect of indomethacin tocolysis in preterm labour on perinatal outcome: a randomised placebo-controlled trial.

OBJECTIVE: To determine whether indomethacin tocolysis in preterm labour is associated with a better perinatal outcome than placebo. DESIGN: A randomised placebo-controlled trial. SETTING: Two university teaching hospitals with level three neonatal intensive care units. POPULATION: Women in preterm labour with intact membranes between 23 and 30 weeks of gestation. METHODS: Random allocation to tocolysis with indomethacin (50 mg followed by 25 mg 6 hourly for 48 hours) or placebo in a double-blind fashion. MAIN OUTCOME MEASURES: The primary outcome, perinatal mortality or severe neonatal morbidity, was defined as perinatal death, necrotising enterocolitis, bronchopulmonary dysplasia, intraventricular haemorrhage or peri-ventricular leucomalacia. Data were analysed using odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: Between March 1995 and February 1996, 34 women (39 babies) were recruited. The baseline characteristics of the two groups were similar. No patient was lost to follow up. In the indomethacin group, gestation was prolonged by > 48 hours in 13/16 (81%) of women vs 10/18 (56%) in the placebo group. The incidence of perinatal mortality or severe neonatal morbidity was not significantly different between the groups, but occurred in twice as many babies in the indomethacin group as in the placebo group--6/19 (32%) vs 3/20 (15%) OR (95% CI) 2.62 (0.44-18.8). There was one perinatal death, of a baby delivered at 24 weeks of gestation. This occurred in the indomethacin group. CONCLUSION: There is no evidence that indomethacin tocolysis is beneficial, and further trials are needed to assess the impact of indomethacin tocolysis in preterm labour.

Does endothelin-1 reduce superior mesenteric artery blood flow velocity in preterm neonates?

AIM: To compare plasma endothelin-1 (ET-1) concentrations in preterm neonates from pre-eclamptic and normal mothers; and to evaluate whether ET-1 has a role in altered arterial blood flow velocity. METHODS: Umbilical arterial blood and neonatal arterial blood were sampled on days 1 and 3 for gas analysis and measurement of plasma ET-1. Doppler ultrasonography of the middle cerebral, renal, and superior mesenteric arteries (SMA) was performed. RESULTS: Neonates in the pre-eclampsia (n = 18) and control (n = 18) groups had mean (SD) gestational ages of 31.1 (2.5) weeks and 30.4 (2.1) weeks; their birth-weights were 1432 (SD 676) g and 1692 (SD 500) g, respectively. In the pre-eclampsia group mean umbilical arterial PO2 was lower--1.88 (0.75) kPa compared with 3.27 (1.41) kPa (p < 0.01)--and mean plasma ET-1 concentration was higher in the umbilical artery--40.6 (SD 15.0) compared with 30.5 (SD 13.8) pg/ml (p = 0.04) and day 1 blood--54.9 (35.0) pg/ml compared with 33.6 (14.6) pg/ml (p = 0.03). Middle cerebral artery peak systolic velocity was higher and SMA time averaged, peak systolic, and mean peak velocities were lower in the pre-eclampsia group. SMA time averaged velocity was inversely related to plasma ET-1 concentration. CONCLUSION: The association between increased production of ET-1 and reduction in SMA time averaged velocity suggests a possible mechanism for hypoperfusion of the intestinal wall in neonates.

Risk and predictors for pregnancy-related complications in women with heart disease.

BACKGROUND: The physiological changes of pregnancy can result in cardiovascular complications in the mother, which in turn may have fetal implications. Prior studies have focused on specific cardiac lesions or identified univariate predictors. There is a need to refine the risk stratification of women with heart disease so they can receive appropriate obstetrical counseling and care. METHODS AND RESULTS: We examined the outcomes of 221 women with heart disease who underwent 276 pregnancies and received their obstetrical care at three Toronto hospitals from 1986 through 1994. Those who underwent therapeutic abortions were excluded. Among the study participants, there were 24 miscarriages and 252 completed pregnancies (pregnancies not ending in miscarriage). Maternal heart failure, arrhythmia, or stroke occurred in 45 completed pregnancies (18%). There were no maternal deaths. Poor maternal functional class or cyanosis, myocardial dysfunction, left heart obstruction, prior arrhythmia, and prior cardiac events were predictive of maternal cardiac complications. These predictors were incorporated into a point score that can be used to estimate the probability of a cardiac complication in the mother. The rate of cardiac complications for a patient with 0, 1, and >1 of the above factors was 3%, 30%, and 66%, respectively. Neonatal complications occurred in 42 completed pregnancies (17%). Neonatal events included death (2), respiratory distress syndrome (16), intraventricular hemorrhage (2), premature birth (35), and small-for-gestational-age birth weight (14). Poor maternal functional class or cyanosis was predictive of neonatal events. CONCLUSIONS: Despite low maternal and neonatal mortality, pregnancy in women with heart disease is associated with significant cardiac and neonatal morbidity. The probability of maternal cardiac or neonatal events can be predicted from baseline characteristics of the mother.

Counseling sexually active teenagers treated with potential human teratogens.

Adolescents with hemoglobinopathies need daily chelation therapy with drugs which are known or suspected to be teratogenic. The prevention of fetal exposure to such drugs is therefore a major task for health professionals caring for these patients. We describe a pilot program aiming to prevent pregnancy among sexually active adolescents treated with iron chelators in Toronto. Most of them had normal response to GnRH, suggesting endocrinologic fertility, and unlike the literature concerning their healthy peers, all sexually active patients in this study reported use of at least one form of contraception.

Doppler velocimetry of the fetal middle cerebral and renal arteries: interobserver reliability.

Using color and pulsed Doppler ultrasonography, the interobserver reliability of measurements in the fetal circulation was evaluated in 41 pregnancies of 25 to 39 weeks' gestation. Two observers recorded flow velocity waveforms from the middle cerebral and renal arteries for measurement of peak systolic, minimum diastolic, and mean velocities, pulsatility index, and resistive index. Intraclass correlation coefficient of reliability was calculated by analysis of variance. Substantial interobserver agreement was found for pulsatility index and minimum diastolic velocity in both arteries. Therefore, these measurements have the greatest clinical applicability.

Ovarian effects upon maternal glucose tolerance.

Ovaries from homozygous diabetic (db/db) female mice were removed and transplanted into the empty left ovarian sacs of normal homozygous (m/m) female mice which had undergone left oophorectomies. To produce controls, the previously removed normal left ovaries were transplanted into the empty left ovarian sacs of other normal (m/m) left oophorectomized females. Glucose tolerance tests were done on the study and control mice before surgery, after surgery, during pregnancy, and after delivery. There were no significant differences in the glucose tolerance test results between study group and controls before or after surgery. However, the study group, when compared to the controls, had a statistically significant glucose intolerance during pregnancy. After delivery, the glucose levels returned to normal. The ovaries from diabetic (db/db) female mice may produce hormones which, by themselves or in concert with the fetal and placental hormones, may produce maternal glucose intolerance during pregnancy.

The prognostic factors in the prenatal diagnosis of the echogenic fetal lung.

The prenatal diagnosis of an echogenic fetal lung (EFL) is now often made in the early second trimester using high-resolution ultrasound. This ultrasound appearance is usually caused by a congenital cystic adenomatoid lung malformation (CCAM), an intrapulmonary lung sequestration or obstruction of a major airway. In order to provide prognostic guidelines to parents who may be considering termination of a fetus with these findings, we have analysed a series of 11 cases diagnosed in our centre over the past 2 years in conjunction with 60 cases from major published series. The data suggest that in the absence of non-immune hydrops fetalis (NIHF) or other anomalies, the outcome for the fetuses is excellent, with over 90 per cent survival. Neither early diagnosis (24 weeks) nor the presence of mediastinal shift is a poor prognostic indicator. In addition, it appears that if NIHF is absent at diagnosis, the chance that it will develop as the pregnancy continues is small (6 per cent). Furthermore, there is a significant (up to 30 per cent) chance that this ultrasound finding will resolve in utero. The development of in utero fetal surgical techniques may be the only hope for those hydropic fetuses who appear to have a dismal prognosis.

Gestational diabetes diagnostic criteria: long-term maternal follow-up.

OBJECTIVE: The purpose of this study was to determine if the risk of having diabetes later in life was different in those who were gestational diabetic by Coustan criteria and not by National Diabetes Data Group criteria and those who are gestational diabetic only by National Diabetes Data Group criteria. STUDY DESIGN: Between 1988 and 1990, 331 patients from the Springfield area who were diagnosed as gestational diabetic by either criteria since 1975 were examined for the development of diabetes by history or by 2-hour, 75 gm glucose tolerance test. National Diabetes Data Group criteria were used to determine normality or diabetic abnormality. Variables associated with diabetes were obtained. The data were analyzed using three groups: (1) gestational diabetic by National Diabetes Data Group criteria, (2) gestational diabetic by Coustan's criteria only, and (3) both groups 1 and 2. RESULTS: Group 1 had 190 (57.4%) and group 2 had 141 patients (42.6%), of which 25.3% and 25.5% had diabetic abnormality, respectively. Variables predictive for the development of diabetic abnormality were glucose tolerance test fasting value, number of gestational diabetic pregnancies, time to follow-up, and prepregnancy weight index. There were no differences in these variables between the normal patients or those with diabetic abnormality in groups 1 and 2. CONCLUSION: Because Coustan criteria classify an additional 68.9% patients who have the same risk and risk factors for later development of diabetic abnormality and pregnancy complications compared with patients who are gestational diabetic by National Diabetes Data Group criteria, the criteria of Carpenter and Coustan should be adopted as the standard for diagnosing gestational diabetes.

Uterine and umbilical blood flow velocity during epidural anaesthesia for caesarean section.

The purpose of this study was to use colour Doppler to determine the effect of epidural anaesthesia on the uterine and umbilical blood flow velocities. After determining the precision of the technique, Doppler insonation of the uterine and umbilical arteries was performed in consenting non-labouring patients requesting epidural anaesthesia for Caesarean section. Patients in Group I were normal and those in Group II were at high risk for uteroplacental blood flow abnormalities. The pulsatility indexes (PI) of both uterine and umbilical arteries were compared at the following times: control, after fluid and after anaesthesia using repeated measure analysis of variance. In Group I (n = 30) the PI increased from 0.72 to 0.82 in the left uterine artery and from 0.71 to 0.85 in the right uterine artery (P < 0.05). In Group II (n = 10) the PI increased from 0.67 to 0.85 in the left uterine artery (NS) and from 0.98 to 1.38 in the right uterine artery (P < 0.05). There was no change in the PI in the umbilical artery. We conclude that the PI of the uterine arteries increases after epidural anaesthesia with lidocaine, epinephrine and fentanyl but there is no change in the umbilical PI. While these changes do not appear to be clinically important in the low-risk population, further studies are required to determine the impact on fetuses at high risk for in utero hypoxaemia.

Ultrastructural localization of filamentous actin within neuronal interphase nuclei in situ.

Previous biochemical studies utilizing isolated nuclei and nuclear matrices have shown actin to be a constituent of the interphase nucleus. In addition, recent ultrastructural work has shown the presence of actin and myosin within nuclei of interphase cells in situ. It was unclear, however, whether this intranuclear actin is present in the unpolymerized globular actin or the filamentous (F)-actin form. The present work, using confocal microscopy and ultrastructural cytochemical techniques, demonstrates the presence of F-actin within interphase nuclei of intact, uncompromised, dorsal root ganglion neurons in vitro and in vivo. Labeling by FITC-phalloidin detected the presence of intranuclear F-actin adjacent to the nucleolar periphery in a small fraction of cells in vitro, an observation confirmed by three-dimensional reconstruction. Ultrastructural analyses of cells exposed to heavy meromyosin (HMM), showed the presence of typical "arrowhead" complexes. The observation that these complexes were associated with nucleoli confirms that the intranuclear ligand detected by FITC-phalloidin indeed represents F-actin. Postembedding labeling with HMM conjugated to 20-nm colloidal gold (HMM-Au20) resulted in labeling similar to that obtained with HMM. However, HMM-Au20 was found to label a much larger fraction of cells, both in vitro and in vivo, than did FITC-phalloidin or HMM. This finding indicates that labeling with HMM-Au20 more accurately reflects the extent of actin polymerization in nuclei. Results from double labeling with HMM-Au20 and an antibody to alpha-sarcomeric actin confirmed that only a small amount of nuclear actin is in the F-form. Together, these results represent a first ultrastructural demonstration of the presence of F-actin in nuclei of neurons. While the role of nuclear F-actin has yet to be defined, the results suggest that F-actin may represent a component of the molecular motor responsible for the dynamic positioning of specific chromatin domains into the tissue-specific, nonrandom patterns observed in many cell types.

Effect of labor on lymphocyte subsets in full-term neonates.

PROBLEM: To determine the effect of labor on lymphocyte subsets in full-term neonates. METHOD OF STUDY: Cord blood obtained at delivery from full-term neonates, six born vaginally and six born by elective Cesarean section, was analyzed for lymphocyte subsets. Monoclonal antibodies, immunofluorescence, and flow cytometry were utilized to determine the lymphocyte phenotype frequencies in these neonates. These frequencies were compared by mode of delivery and to adult peripheral blood reference ranges using a two-tailed Student's t-test, P < 0.05. RESULTS: A profile of significantly elevated T (CD2, CD3) and helper cells (CD4) and depressed Natural Killer cells (CD16, CD56) is characteristic of term Cesarean section neonates. Significantly depressed frequency of T cells (CD2, CD3) and helper T cells (CD4) and elevated Natural Killer cells (CD16, CD56) is characteristic of vaginally delivered neonates. CONCLUSIONS: The mode of delivery affects the lymphocyte subset frequencies in full-term neonates.

The effect of minor degrees of glucose intolerance on the incidence of neonatal macrosomia.

The incidence of neonatal macrosomia in infants of mothers who have only one abnormal value in a 3-hour glucose tolerance test (GTT) is greater than normal. Often, corrections for gestational age have not been used in the analysis, and in the few studies in which corrections were made, the results conflicted. In this study, the birth weights of infants from 157 patients who had only one abnormal GTT value were compared with the birth weights of infants from normal mothers, with and without correction for gestational age. Analysis using three different GTT criteria revealed that the incidence of birth weight greater than 4000 g was 20% or greater in the infants of mothers who had only one abnormal GTT value and only 12.4% in controls. However, when adjusted for gestational age, there were no differences in the birth weights and percentage of large for gestational age (LGA) infants in the study groups versus controls. The mean and gestational age-adjusted birth weights of the greater-than-4000-g neonates born to women with one abnormal GTT value were no different than those of controls. However, at delivery, the gestational ages of patients with one abnormal GTT value tended to be slightly greater than those of controls by 0.1-0.6 weeks, suggesting that minor degrees of abnormal glucose metabolism may prolong pregnancy in some patients. When compared with the literature, the findings of this study suggest that the National Diabetes Data Group criteria may be too high as a screen for LGA infants.

Prevention of neonatal macrosomia in gestational diabetes by the use of intensive dietary therapy and home glucose monitoring.

This study was undertaken to determine if intensive dietary therapy, home blood glucose monitoring, and the selective use of insulin can be effective in preventing fetal macrosomia. All patients were screened at 24 to 28 weeks' gestation using a modification of O'Sullivan's criteria. The 153 patients diagnosed as gestational diabetics by the study protocol were placed on a 1800 to 2000 Kcal American Diabetes Association diet and taught home glucose monitoring. Insulin therapy was initiated only if blood glucose control was inadequate. There were no significant differences (p greater than 0.05) between the study and reference populations in regard to mean birthweight or the incidence of macrosomia. Since our study criteria for diagnosing gestational diabetes were slightly different from those of the National Diabetes Data Group (NDDG), data from 99 patients meeting the NDDG criteria were analyzed in a similar manner. No significant differences were found between this subgroup and the reference population. Since only 7.2% of our study patients required insulin, we conclude that the incidence of fetal macrosomia in gestational diabetes can be kept equal to that of the general population by a program of intensive dietary therapy and home glucose monitoring, with insulin being used only therapeutically, not prophylactically.

Effect of pregnancy on glucose metabolism in glucose intolerant 'BB' Wistar rats.

Little is known about the effect of pregnancy on the 'BB' Wistar rat, an animal model of insulin-dependent (type I) diabetes. The pathogenesis of diabetes in this animal model seems to result from antibody-mediated natural killer cell destruction of pancreatic beta cells. The glucose metabolism of glucose intolerant female rats (study group) was studied prior to pregnancy, during pregnancy, and postpartum using glucose tolerance tests (GTT). Control rats with normal GTT were studied and bred in a fashion similar to the study animals. Before becoming pregnant, the GTT levels of the chemically diabetic rats were significantly different from those of the controls (p less than 0.05). The GTT values of the study animals decreased during pregnancy to levels seen in pregnant controls. After pregnancy, the GTT values of the study animals returned to prepregnant levels. Based on these observations, it appears that pregnancy may block the autoimmune destruction of beta cells, causing an increase in insulin production and release, thereby improving glucose metabolism.