Paul P. van den Berg

Maturation of the human fetal brain as observed by 1H MR spectroscopy.

Proton MRS was used to monitor cerebral metabolite tissue levels in 35 normal fetuses during development in the gestational age range of 30–41 weeks. First, MRI in three orthogonal orientations was performed. A volume of interest (VOI) (15–43 cc) of fetal brain tissue was then selected for 1H MRS. For localization, two pulse sequences (stimulated echo acquisition mode (STEAM) at TE = 20 ms, and point‐resolved spectroscopy (PRESS) at TE = 135 ms) were applied. The MR spectra of the brain showed signals for inositol (Ino), choline (Cho), creatine (Cr), and N‐acetyl (NA) compounds. From 30 to 41 weeks the absolute tissue level of NA, and the ratios of NA/Cr and NA/Cho increased, whereas the ratio of Cho/Cr decreased. These changes reflect maturation of the brain. Considering the diagnostic value of proton MRS in pediatric neurology, this new approach may also be useful for characterizing pathological conditions in the fetal brain. Magn Reson Med 48:611–616, 2002.

Risk for surviving twin after fetal death of co-twin in twin-twin transfusion syndrome

Objective To determine neonatal outcome of surviving twins in pregnancies complicated by twin-twin transfusion syndrome and fetal deaths of co-twins. Methods We retrospectively reviewed medical records of 11 women seen during 1990–1996 in our hospital who had pregnancies complicated by twin-twin transfusion syndrome and death of one fetus. Results The median interval between fetal death and delivery (six by cesarean delivery and five vaginally) was 2 weeks (range, 1 day to 7 weeks). Three of the 11 surviving twins died soon after birth (gestational ages at birth 32, 31, and 34 weeks; fetal death-delivery intervals 3, 7, and 7 weeks, respectively). Two survivors were severely handicapped (gestational ages at birth 29 and 33 weeks; fetal death-delivery interval 1 and 2 weeks, respectively). Two children showed cerebral echodensities on ultrasound after birth but developed normally, and four did not show any abnormalities on cerebral and abdominal ultrasound and developed normally. Five of 11 surviving twins, each born 1 week or more after fetal death of the co-twin, either died or experienced serious morbidity. In the two infants born within 1 day of fetal death, no problems were detected. Conclusion In monochorionic twin gestations complicated by twin-twin transfusion syndrome, approximately half of surviving twins will experience mortality or serious morbidity when co-twins die in utero.

Neonatal complications in newborns with an umbilical artery pH <7.00

OBJECTIVE Our purpose was to determine the significance of an umbilical artery pH < 7.00 in relation to neonatal morbidity and mortality. STUDY DESIGN Between 1986 and 1993 acid-base assessment of the umbilical artery was performed routinely in 10,699 deliveries. In a retrospective cohort study 84 nonanomalous neonates with an umbilical artery pH < 7.00 were individually matched with 84 neonates with an umbilical artery pH > 7.24. Matched variables included year of delivery, gender, parity, maternal age, delivery mode, fetal presentation, gestational age, and birth weight. Differences in morbidity between the two groups during the neonatal period (until 28 days after delivery) were investigated. RESULTS Neonates with an umbilical artery pH < 7.00 versus > 7.24 showed significant differences in the following: neonatal condition directly post partum; neurologic, respiratory, cardiovascular, and gastrointestinal complications; and neonatal intensive care unit admissions. No significance was found in renal dysfunction and mortality rate. The proportion of premature infants (< 37 weeks) was 17% in both groups. In the acidotic group a 1-minute Apgar score < or = 3 and a 5-minute Apgar score < 7 was predictive for neonatal complications. CONCLUSIONS Severe intrapartum asphyxia, quantified by an umbilical artery pH < 7.00, poses a threat to the neonates health.

Maternal Allopurinol During Fetal Hypoxia Lowers Cord Blood Levels of the Brain Injury Marker S-100B

BACKGROUND: Fetal hypoxia is an important determinant of neonatal encephalopathy caused by birth asphyxia, in which hypoxia-induced free radical formation plays an important role. HYPOTHESIS: Maternal treatment with allopurinol, will cross the placenta during fetal hypoxia (primary outcome) and reduce S-100B and free radical formation (secondary outcome). METHODS: In a randomized, double-blind feasibility study, 53 pregnant women in labor (54 fetuses) with a gestational age of >36 weeks and fetal hypoxia, as indicated by abnormal/nonreassuring fetal heart rate tracing or fetal scalp pH of <7.20, received 500 mg of allopurinol or placebo intravenously. Severity of fetal hypoxia, brain damage and free radical formation were assessed by arterial cord blood lactate, S-100B and non-protein-bound-iron concentrations, respectively. At birth, maternal and cord blood concentrations of allopurinol and its active metabolite oxypurinol were determined. RESULTS: Allopurinol and oxypurinol concentrations were within the therapeutic range in the mother (allopurinol > 2 mg/L and/or oxypurinol > 4 mg/L) but not always in arterial cord blood. We therefore created 3 groups: a placebo (n = 27), therapeutic allopurinol (n = 15), and subtherapeutic allopurinol group (n = 12). Cord lactate concentration did not differ, but S-100B was significantly lower in the therapeutic allopurinol group compared with the placebo and subtherapeutic allopurinol groups (P < .01). Fewer therapeutic allopurinol cord samples had measurable non–protein-bound iron concentrations compared with placebo (P < .01). CONCLUSIONS: Maternal allopurinol/oxypurinol crosses the placenta during fetal hypoxia. In fetuses/newborns with therapeutic allopurinol/oxypurinol concentrations in cord blood, lower plasma levels of the brain injury marker protein S-100B were detected. A larger allopurinol trial in compromised fetuses at term seems warranted. The allopurinol dosage must be adjusted to achieve therapeutic fetal allopurinol/oxypurinol concentrations.

Antenatal proton MR spectroscopy of the human brain in vivo

IntroductionThe assessment of metabolites in the human fetal brain in utero could have diagnostic value. We explored the feasibility and potentials of proton magnetic resonance spectroscopy (1H MRS) for this purpose.Results1H MRS was successfully performed in the third trimester of pregnancy without using sedation. Signals for inositol, choline, creatine, and N-acetylasparatate (NAA) compounds were detected in MR spectra from single voxels in the brain. Absolute tissue levels of these metabolites resemble values measured in preterm and term babies, especially of relatively more mature brain regions, from which most of the MR spectra have been obtained. Brain maturation between 30 and 41 weeks of gestation was most clearly reflected by increasing levels of the neuronal marker NAA.ConclusionWith proper care for the methodological aspects, antenatal 1H MRS clearly has the potential to evolve into a clinical tool for assessing a number of key metabolites in the human fetal brain in utero.

Accuracy of serum uric acid as a predictive test for maternal complications in pre-eclampsia: Bivariate meta-analysis and decision analysis

The aim of this study is to determine the accuracy and clinical value of serum uric acid in predicting maternal complications in women with pre-eclampsia. An existing meta-analysis on the subject was updated. The accuracy of serum uric acid for the prediction of maternal complications was assessed with a bivariate model estimating a summary Receiver Operating Characteristic (sROC) curve. Subsequently, a clinical decision analysis was performed, in which three alternative strategies were modelled: (I) expectant management with monitoring until spontaneous labour; (II) induction of labour; (III) serum uric acid as test for predicting maternal complications. In the latter strategy, accuracy data of serum uric acid derived from the sROC curve were used to assess the value of serum uric acid in the management of women with pre-eclampsia. In this strategy, women with an increased serum uric acid were supposed to have labour induced, whereas women with serum uric acid levels below the threshold were managed expectantly. The decision whether to use the policy expectant management, to induce labour or to test serum uric acid levels, is based on the expected utility of each strategy. The expected utility depends on the probability of occurrence of severe maternal complications (i.e. severe hypertension, haemolysis, elevated liver enzymes and low platelet count (HELLP syndrome) or eclampsia) and the mode of delivery (caesarean section versus vaginal delivery). Valuation of the outcomes was performed using a distress ratio, which expresses how much worse a complication of pre-eclampsia is valued as compared to a caesarean section. Eight studies, testing 1565 women with pre-eclampsia, met the inclusion criteria. If the distress ratio was 10, the strategy regarding serum uric acid would be the preferred strategy when the probability of complications was between 2.9 and 6.3%. At higher complication rates induction of labour would be preferred, whereas at lower complication rates expectant management would be the best treatment option. These findings were stable in sensitivity analyses, using different distress ratios. Based on the decision analysis, serum uric acid seems to be a useful test in the management of pre-eclampsia under realistic assumptions.

The attitude of women toward current and future possibilities of diagnostic testing in maternal blood using fetal DNA

To determine the opinions of women about the new developments in the field of noninvasive prenatal diagnosis (NIPD).

Immediate delivery versus expectant monitoring for hypertensive disorders of pregnancy between 34 and 37 weeks of gestation (HYPITAT-II): an open-label, randomised controlled trial

BACKGROUND There is little evidence to guide the management of women with hypertensive disorders in late preterm pregnancy. We investigated the effect of immediate delivery versus expectant monitoring on maternal and neonatal outcomes in such women. METHODS We did an open-label, randomised controlled trial, in seven academic hospitals and 44 non-academic hospitals in the Netherlands. Women with non-severe hypertensive disorders of pregnancy between 34 and 37 weeks of gestation were randomly allocated to either induction of labour or caesarean section within 24 h (immediate delivery) or a strategy aimed at prolonging pregnancy until 37 weeks of gestation (expectant monitoring). The primary outcomes were a composite of adverse maternal outcomes (thromboembolic disease, pulmonary oedema, eclampsia, HELLP syndrome, placental abruption, or maternal death), and neonatal respiratory distress syndrome, both analysed by intention-to-treat. This study is registered with the Netherlands Trial Register (NTR1792). FINDINGS Between March 1, 2009, and Feb 21, 2013, 897 women were invited to participate, of whom 703 were enrolled and randomly assigned to immediate delivery (n=352) or expectant monitoring (n=351). The composite adverse maternal outcome occurred in four (1·1%) of 352 women allocated to immediate delivery versus 11 (3·1%) of 351 women allocated to expectant monitoring (relative risk [RR] 0·36, 95% CI 0·12-1·11; p=0·069). Respiratory distress syndrome was diagnosed in 20 (5·7%) of 352 neonates in the immediate delivery group versus six (1·7%) of 351 neonates in the expectant monitoring group (RR 3·3, 95% CI 1·4-8·2; p=0·005). No maternal or perinatal deaths occurred. INTERPRETATION For women with non-severe hypertensive disorders at 34-37 weeks of gestation, immediate delivery might reduce the already small risk of adverse maternal outcomes. However, it significantly increases the risk of neonatal respiratory distress syndrome, therefore, routine immediate delivery does not seem justified and a strategy of expectant monitoring until the clinical situation deteriorates can be considered. FUNDING ZonMw.

Use of insulin like growth factor binding protein-1 in the diagnosis of ruptured fetal membranes.

OBJECTIVE The benefit of insulin like growth factor binding protein-1 (IGFBP-1) in diagnosing ruptured fetal membranes in cases in which the diagnosis is clinically doubtful, is investigated. DESIGN A total of 83 patients with clinically doubtful rupture of fetal membranes were included, and treated as usual. The clinical diagnosis, the amniotic fluid crystallization test, and IGFBP-1 detection were performed on all patients and compared with the defined gold standard. The sensitivity, specificity, positive predictive value, and negative predictive value of each test were calculated. RESULTS In all, 27 patients (33%) had ruptured fetal membranes at the time of inclusion. The clinical diagnosis of the attending obstetrician showed a higher predictive value of both a positive and negative test result than both IGFBP-1 detection, and the amniotic fluid crystallization test. CONCLUSIONS As the clinical diagnosis showed the highest sensitivity and specificity, IGFBP-1 detection has no additional benefit to ascertain the diagnosis of ruptured fetal membranes in cases in which the diagnosis was clinically doubtful.

Proton magnetic resonance spectroscopy of human fetal brain

In vivo proton magnetic resonance spectroscopy of human fetal brain was performed in the third trimester of pregnancy. Spectra were obtained showing signals assigned to cerebral compounds such as N-acetylaspartate, creatine, and cholines. Relative signal intensities were similar to those observed in neonatal brain spectra recorded during the early postnatal stage.