Volume 33, Issue 1

Functional genomics (transcriptomics and proteomics) is a global, systematic and comprehensive approach to the identification and description of the processes and pathways involved in normal and abnormal physiological states. The functional genomics methods most applied today are DNA microarrays and proteomics methods, primarily two-dimensional gel electrophoresis coupled with mass spectrometry. To date, interesting research has been carried out, representing milestones for future implementation of functional genomics/proteomics in perinatal medicine. For instance, possible biomarkers of pre-eclampsia, preterm labor and gestational trophoblastic diseases have been discovered. Further systematic examination of differentially regulated genes and proteins in maternal and fetal tissues and fluids will be required. However, high-throughput technologies reflect biological fluctuations and methodological errors. Large amounts of such different data challenge the performance and capacity of the statistical tools and software available at present. Further major developments in this field are pending and the intellectual investment will certainly result in clinical advances.

Objective: Fetal hypoxia and preterm delivery are reported to be strongly associated with brain damage and neurodevelopmental delay. Doppler signs of fetal brain sparing have been described during chronic hypoxia, but whether they are related to brain damage is unknown. The aim of this study was to evaluate if markers of tissue injury, i.e., tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) are related to signs of increased perinatal vascular impedance and/or fetal brain sparing in high-risk pregnancies. Study design: TNF-α and IL-6 levels were evaluated in maternal blood serum of 67 high-risk pregnancies. Serum samples were taken at the time of umbilical, middle cerebral artery and uterine artery Doppler velocimetry examination. The values for TNF-α and IL-6 were correlated with reference median values obtained with gestational age in the form of a Z-score. Results: TNF-α levels showed values within the normal range in only four cases. IL-6 values were found normal in 14 cases. The Z-score for mean middle cerebral artery pulsatility index (PI) showed a significant correlation to TNF-α and IL-6 levels, P<0.0001 and P<0.003, respectively. This might suggest a strong correlation between signs of fetal brain sparing and increased maternal serum TNF-α and IL-6 levels. Abnormal uterine artery PI and the presence of a “notch” were also highly significantly related to TNF-α and IL-6 levels, which were nearly two-fold higher compared to normal uterine artery blood flow and the absence of a “notch”. Abnormal cerebro/placental ratios showed significant correlations to TNF-α and IL-6 levels. Conclusion: The present results suggest a strong correlation between levels of TNF-α and IL-6 not only for signs of fetal brain sparing, but also for uteroplacental blood flow. This finding supports the role of tissue injury in cases of fetal brain sparing, but whether this is a reflection of brain damage or secondary to placental pathology needs further evaluation.

Objective : The association between elevated interleukin (IL)-8 concentrations in amniotic fluid and preterm delivery is well described. Little consideration has been given to the impact of different groups of microorganisms within the amniotic cavity on IL-8 concentration. Methods : We collected amniotic fluid, placental tissue and amniotic membranes during preterm cesarean sections for bacterial culture. In addition, we determined IL-8 concentrations in maternal serum, amniotic fluid and cord blood and correlated them with the various intra-amniotic pathogens isolated by bacterial culture. Results : IL-8 concentrations were determined in amniotic fluid in 107 cases, in cord blood in 185 cases and in maternal blood in 158 cases. Women with intra-amniotic Ureaplasma urealyticum infection had significantly higher amniotic fluid concentrations of IL-8 than those without (P<0.001). In cord blood, we found significantly elevated IL-8 concentrations due to intra-amniotic infection with U. urealyticum (P=0.045) and other pathogens (P=0.04). In maternal sera, we found no significant elevation of maternal IL-8 in any of the groups. Conclusion : Intrauterine infection with U. urealyticum seems to play a profound role in the cascade of inflammation and increases IL-8 concentrations in amniotic fluid and cord blood.

Objective: Intrinsically poor maternal adaptation to pregnancy and dysregulated processes have been postulated to occur as a consequence of an immune response to the feto-placental unit as “foreign” material. The aim of our study was to compare placental pathology and pregnancy outcomes of in vitro fertilization (IVF) pregnancies conceived by donor oocytes with those conceived by non-donor oocytes. Study design: We conducted a retrospective, case-control study on 91 placentas from IVF pregnancies (36 from donor oocytes and 55 from non-donor cycles). All placentas were examined by a single pathologist for signs indicative of an immune response, including chronic villitis, chronic deciduitis, increased perivillous fibrin, ischemic change/infarction, decidual vasculopathy, increased syncytial knots, intervillous thrombi, and retroplacental hematomas. Results: Placentas from donor cycles were significantly more likely to demonstrate certain pathologic findings: chronic villitis (P<0.001), chronic deciduitis (P=0.034), increased perivillous fibrin (P=0.001), ischemic change/infarction (P=0.001), and intervillous thrombi (P=0.008). There was no statistical significance with respect to decidual vasculopathy, increased syncytial knots, or retroplacental hematomas. Conclusion: Pathologic evidence of an immune-mediated process is much more pronounced in donor oocyte IVF pregnancies compared to non-donor cycles. Clinical implications of these findings have yet to be determined.

Objective : To investigate whether the blink-startle reflex (BSR) is a good marker of habituation to vibroacoustic stimulation in healthy preterm fetuses. Materials and methods : A total of 22 women with uncomplicated pregnancies at 30–34 weeks participated in the study. Vibroacoustic stimulus was repeatedly applied to the maternal abdomen above the fetal head for a period of 2 s every 10 s. Fetal eye tightening monitored by ultrasound within 2 s of the stimulus was considered a positive response. The habituation rate was defined as the number of stimuli applied before the fetus stopped responding to two consecutive stimuli. Results were compared using the Mann-Whitney U -test. Results : All 22 fetuses showed habituation at a rate that varied from 1 to 9 (mean 4.2±1.8). Conclusion : BSR is a good marker of habituation in preterm fetuses. Further study is needed to ascertain whether abnormal BSR habituation could be a sign of fetal distress.

Aims : This study reports the changes in patterns of fetal breathing movements recorded with a photogrammetric method in three successive periods of gestation. Methods : Respiratory movements were studied in fetuses of 28 healthy women with uncomplicated pregnancies of 30–38 weeks of gestation. Women were divided into three groups according to gestational age of the fetus: 30–32 weeks, 7 fetuses; 33–36 weeks, 9 fetuses; and 37–38 weeks, 12 fetuses. Sonographic images of the fetuses were recorded on videotape, digitized (1 image per 0.12 s) and analyzed with specially developed software. Results : The proportion of fetuses in each age group for which movements were detectable was similar in all three groups, as was the frequency of movements. Duration of a complete respiratory cycle, the inspiratory phase and the expiratory phase tended to be shorter at 33–36 weeks of gestation than in younger and older fetuses. Fetuses in the 30–32-week group had slower breathing rates than fetuses in the two older groups. Conclusions : The photogrammetric technique revealed differences in some patterns of fetal breathing movements between weeks 30–32, 33–36 and 37–38 of gestation. The data provide a sound basis for relating changes in fetal breathing movements with physiological and anatomical changes that occur as the respiratory system matures.

Objective : The purpose of our study was to investigate any possible relationship between the duration of labor, the mode of delivery and the duration of rupture of membranes and hematological parameters in cord blood. Material and methods : We studied 298 pregnant women who delivered term normal infants. The patients were divided into three groups according to the route of delivery: vaginal (n=165), cesarean section after labor (n=27) and elective cesarean section (n=106). Immediately after delivery, umbilical cord blood samples were collected. Results : The mode of delivery influenced white blood cells, hemoglobin, hematocrit, red blood cell distribution, platelets count and nucleated red blood cells. There was no correlation between the cord blood hematological values and the duration of labor, as well as the duration of rupture of membranes before delivery. Conclusion : The influence of mode of delivery, duration of labor and duration of ruptured membranes on hematological parameters in umbilical cord blood is limited.

Aim : The aim of the study was to observe different expressions and movements of a fetal face during investigation of fetal behavior in the second and the third trimester of normal pregnancies, as a probable manifestation of fetal awareness. Subjects and methods : Over a 6-month period a study was conducted in three centers in Zagreb, Croatia and in Barcelona and Malaga, Spain. Women with singleton pregnancies (16–33 weeks) who were referred for ultrasound check-up for determination of gestational age, suspicious fetal malformations, polyhydramnios, and/or the assessment of biophysical profile or other possible pathology, were assigned to the study. After regular two-dimensional (2D) ultrasound assessment at an antenatal clinic, pregnant women were offered the possibility of undergoing 4D ultrasound examination if the fetus and the mother were considered “normal”, i.e., if ultrasound and clinical assessment were uneventful. If the newborn delivered at term had 1- and 5-min Apgar scores of 7 and 10, respectively, and if the newborn was considered “term and normal” (normal spontaneous activity, normal posture and tone, and presence of some primitive reflexes) at the first and subsequent regular check-ups, the inclusion criteria were deemed to have been met. Out of 119 patients, 99 fulfilled the inclusion criteria, 40 of whom were in the second, and 59 in the third trimester of pregnancy. A Voluson 730 Expert system with a transabdominal 5-MHz transducer was used for 4D ultra- sonography. After regular 2D scanning, the 4D mode was switched on, and a live 3D image was reconstructed by selecting ideal 2D mid-sagittal images of the face (the region of interest). The volume was automatically scanned every 2 s while the surface-rendered mode was switched on, and 4D images were displayed on the screen and recorded on videotape during a 30-min observation period. Movements of the following fetal face structures were analyzed: forehead, brows, nasal soft tissue and nasolabial folds, upper lip, oral cavity and tongue, lower lip and chin, eyelids and eyes, mouth and mouth angles, and facial expression. 4D ultrasonography allowed in utero observations of fetal facial expressions such as smiling, yawning, and swallowing. Results : The quality of 4D depiction of fetal facial expressions increased with gestational age. The frequency of fetal facial expressions such as yawning ranged from 1 and 6 with a median of 1.5 per 30-min observation period; smiling ranged from 2 and 8 with the median of 2; tongue expulsion ranged from 2 to 6, median 3; mouth and eye squeezing ranged from 5 to 10, median 6; scowling ranged from 1 to 3, median 0.5; and isolated eye blinking ranged from 4 to 12 with a median of 5. Conclusions : Our study shows the ability of 4D sonography to depict different facial expressions and movements, which might represent fetal awareness. Never-theless, long, precise and thorough observation of fetal faces by 4D sonography was hampered as the images were only near real-time. Thus, we were only able to study the quality and not the quantity of facial movement patterns.

Aim : To determine the value of cord blood cardiac troponin I levels (cTnI) as an early prognostic factor in critically ill newborns, and to compare cord cTnI levels with the prognostic value of the score for neonatal acute physiology (SNAP). Methods : Cord arterial samples were collected routinely for blood gas analysis, and cord venous samples for cTnI and cardiac-specific creatine kinase assay. The study group (n=109) comprised critically ill newborns who required mechanical ventilation. The control group (n=96) comprised newborns who were either completely healthy (n=48) or were followed in a level I neonatal care unit due to moderate-severity problems. Results : The critically ill newborns had significantly higher cTnI levels than control babies (median [min-max] 1.4 [0–13] vs. 0 [0–1.8] ng/mL, respectively; P<0.001). In critically ill newborns, non-survivors had significantly higher cTnI levels than survivors (median [min-max] 6.6 [1.3–13.0] vs. 1.3 [0–8.0] ng/mL, respectively; P<0.001). Receiver-operator curve analysis revealed that, compared with SNAP, cTnI was a more sensitive predictor of mortality in critically ill newborns (area under curve=0.96; 95% CI=0.90–1.02). Conclusion : Significantly elevated cord cTnI may be a valuable predictor of mortality in critically ill newborns.

Objective : The neonatal regional tertiary care center of the University of Vienna (VC) has been a member of the Vermont Oxford Neonatal Network (VONN) since 1994. During the period 1994–2002, important differences between the VC and the VONN in both pre- and postnatal management and in late morbidities such as chronic lung disease (CLD) and severe retinopathy of prematurity (ROP) were observed. We hypothesize that stabilization of very-low-birth-weight (VLBW) infants on nasal continuous positive airway pressure (NCPAP) immediately after birth, combined with a restrictive use of artificial ventilation, might be responsible for lower rates of CLD and ROP. Patients and methods : Obstetric and neonatal data for all 1299 VLBW infants (401–1500 g) from the VC were compared with corresponding data for the 201,167 VLBW infants from the VONN for the period 1994–2002 with regard to respiratory management and patient outcome. Morbidity criteria were in accordance with VONN definitions. Results : The percentage range for treatment and morbidity criteria for the VC and VONN are related to differences among various years within the observation period. Infants were stabilized at birth on NCPAP in 45–86% of cases in the VC vs. 37–63% in the VONN, the rate of mechanical ventilation was 40–59% vs. 66–74%, and use of surfactant was 31–50% vs. 55–64%. CLD was diagnosed in 14–32% of cases in the VC vs. 27–39% in the VONN, discharge on supplemental oxygen took place in 2–4% vs. 12–17% of cases and ROP (stages III and IV) was found in 1–10% vs. 8–12%. Conclusion : The association of lower rates of CLD and ROP in the VC compared to the VONN might be related to differences in early respiratory management of VLBW infants at high risk of development of respiratory distress syndrome. This needs to be confirmed in a large multicenter trial.

We report on a 28-week infant with growth restriction starting after 23 weeks' gestation because of measles virus (MV) infection of the mother. Histological findings for the placenta revealed extensive fibrin deposition and necrosis of the villi, and MV antigen was demonstrated in the syncytiotrophoblast by immunostaining. The MV-specific IgM level in the infant was negative, but that of the mother was positive. Therefore, we speculate that growth restriction is not attributed to direct infection with MV, but to placental dysfunction due to a decrease in intravillous blood flow and oxygen supply to the fetus.

We present a case of hemifacial microsomia, first detected by prenatal sonography and confirmed by ultrafast magnetic resonance (MR) imaging. A 26-year-old patient was referred to our hospital at 20 weeks of gestation because of unilateral right-sided ventriculomegaly and of a possible ventriculoseptal defect (VSD). Our sonographic examination suggested a right orbital hypoplasia and a hemiatrophy of the nose. The ultrafast T2-weighted single-shot fast-spin echo MR imaging, demonstrated a right ear hypoplasia (microtia), a right orbital hypoplasia, and a right renal hypoplasia. Epibulbar dermoid or conjunctival lipodermoid were not recognized. The fetus was prenatally diagnosed as hemifacial microsomia. Termination of pregnancy was performed at 21 weeks gestation, and a male baby weighing 342g was stillborn. The baby showed facial asymmetry, including hemiatrophy of the right nose, and right ear hypoplasia. Autopsy revealed a 2mm area of VSD, agenesis of the right kidney and ureter, pancreatic and renal aberration into right adrenal gland, thymus hypoplasia and an unfixed ascending colon without intestinal malrotation. To the best of our knowledge, this is the first report of prenatal diagnosis for hemifacial microsomia using fetal MR imaging. In our case, fetal MR imaging has evolved into a powerful diagnostic tool, for the accurate prenatal diagnosis.

A case of coma due to carbamazepine ingestion with the intention of committing suicide at 33 weeks' gestation is presented. Management included activated charcoal administration and exchange plasmapheresis. A fetal non-stress test was non-reassuring but the Apgar score, cord blood gases and early neonatal outcome were normal. Differential diagnosis of coma in pregnancy should include investigation for drug intoxication.

Meconium peritonitis is a sterile chemical peritonitis caused by peritoneal seeding of meconium from an antenatal gastrointestinal perforation. We report a 32-week preterm female neonate who developed meconium peritonitis due to bowel perforation, secondary to a twisted left fallopian tube mass, which was excised and confirmed by histopathology. This association has not been reported earlier. The infant also developed transient central diabetes insipidus, a very rare condition in a preterm neonate.

Meningoencephalitis in neonatal congenital syphilis (CS) is a difficult diagnosis because of the limitation of standard cerebrospinal fluid (CSF) tests. This limitation means that new markers in CSF tests are needed to establish whether meningitis is present in presumptive cases of CS. β 2 -Microglobulin (β 2 -m) is raised in CSF recovered from neonates with central nervous system (CNS) infections, but it does not correlate with cellular count or proteins in the CSF. We present a preterm newborn with symptomatic CS. First-day CSF showed 50 cells/mm 3 , protein of 220 mg/dL and a β 2 -m concentration of 16.9 mg/dL (normal <2.25 mg/dL). Serial determinations of β 2 -m showed a marked reduction (76%) after 10 days of appropriate treatment. At 30 days of life, β 2 -m was already within the normal range (1.8 mg/dL). Cerebral ultrasonography showed ventricular dilatation, moderate periventricular echogenicity, subependimal hemorrhages, and linear hyperechoic areas in the thalamus and basal ganglia. We suggest that β 2 -microglobulin is very useful in the diagnosis of CNS involvement and in monitoring the response to treatment. In addition, infants with CS may exhibit CNS imaging findings similar to those observed in other intrauterine CNS infections.