Volume 33, Issue 4

The major burden of preterm birth is in the developing world, where much of the death and morbidity is secondary to infectious diseases such as malaria, HIV, tuberculosis and intestinal parasites. There is some evidence to support the concept that normal gestational length varies with ethnic group; babies of black African ancestry tend to be born earlier, more commonly pass meconium in labor, but have less respiratory distress than white European babies of matched gestational age. However, ethnic differences are tiny compared with the effects of infectious disease and malnutrition. Interventions to prevent preterm birth should predominantly be aimed at the prevention and treatment of infectious disease, and the improvement of maternal nutrition. Without this, medical intervention tends to increase the rate of preterm birth without corresponding improvement in outcomes.

Erythropoietin (EPO) treatment for anemia of prematurity is still controversial. Large multicentric trials demonstrate that administration of EPO+Fe cannot prevent early transfusions, particularly in very low birth weight newborns and in infants with severe neonatal diseases, but may have some beneficial effect to prevent late transfusions. Current treatment of anemia of prematurity should be multifactorial trying to minimize all causes that reduce erthrocytic mass (phlebotomies, use of noninvasive procedures) and promoting all factors that increase it (placental transfusion, adequate nutrition support). To evaluate the real impact of EPO treatment it is mandatory to follow similar transfusion protocols for preterm infants in all the studies. The aim of EPO+Fe administration should be to avoid new late transfusions in very low birth weight preterm infants or to prevent the first transfusion after the second week of life in less immature premature with the objective of reducing the number of donors rather than the number of transfusions. We have limited the use of EPO+Fe to infants <30 weeks gestational age and birth weight ≤1250 g as well as to infants weighing 1250–1500 g with initial severe disease. The comparison of outcomes before (28 months period with EPO+Fe treatment to all premature ≤32 weeks gestational age) and after 20 months of implementation of the new protocol showed a significant decrease in EPO+Fe treatment candidates (40.3% vs. 85.9%, P<0.001) without changes in the percentage of transfusions in both periods. Therefore if EPO treatment is to be given it should be limited to preterm infants with a birth weight <1000 g or those of 1000–1250 g associated with risk factors for blood transfusion. It should be started at 3–7 days of life at doses of 250 U/kg subcutaneously, three times a week, for 4–6 weeks depending on gestational age with oral iron 2–12 mg/kg/day to keep ferritin levels greater than 100 ng/mL.

Objective : To assess the quality of studies of nifedipine used to treat spontaneous preterm labor. Design : A systematic review of study quality using a novel validity assessment tool, examining method-specific and topic-specific items in the domains of selection, performance and measurement biases. Data Sources : Medline (1996–2003), EMBASE (1996–2003), BIOSIS (1993–2003), Current Contents (1995–2003), DERWENT DRUGFILE (1983–2003), Cochrane Database of Systematic Reviews. Bibliographies of existing meta-analyses and systematic reviews of nifedipine as a tocolytic. Methods of Study Selection : Forty-five studies evaluating the effectiveness of nifedipine were identified. Data Extraction : Each study was assessed for 40 method-specific and topic-specific items of quality in duplicate using piloted data extraction forms. Disagreements between assessors were settled by consensus/arbitration. Data Synthesis : Very few of the studies complied with adequacy criteria of quality for either method-specific or topic-specific items. There was no improvement in quality over time. The quality of method-specific items was significantly poorer when compared with topic-specific items of quality overall (P<0.0001) and in the domains of selection bias (P<0.0001) and performance bias (P<0.0001). Conclusion : Studies of the effectiveness of nifedipine as a tocolytic are of poorer quality with respect to method-specific items than topic-specific items. These deficiencies should be highlighted in meta-analyses or systematic reviews which measure efficacy and should influence the generation of guideline statements or recommendations for the use of nifedipine as a tocolytic. A large randomized trial fulfilling the quality items is necessary to assess the real efficacy of nifedipine in preterm labor.

Objective: Activation of the complement system has recently been implicated in the mechanisms of fetal loss in the antiphospholipid syndrome. It is, however, possible that complement activation is also involved in other causes of fetal death in the second and third trimesters of pregnancy. We therefore conducted a study to determine whether fetal death is associated with changes in the maternal plasma concentrations of complement split products or anaphylatoxins (C3a, C4a and C5a). Study design: A cross-sectional study was designed to include normal pregnant women (n=60) and patients with fetal death (n=60). Patients with fetal death were classified according to the cause of fetal demise into: a) unexplained (n=44); b) associated with preeclampsia (n=8); and c) associated with chromosomal abnormalities or major congenital fetal anomalies (n=8). The plasma concentrations of C3a, C4a and C5a were measured using sensitive and specific ELISAs. Non-parametric statistics were used for analysis. A P value of <0.05 was considered significant. Results: 1) The median plasma concentration of C5a was higher in patients with fetal death than in normal pregnant women [median 16 ng/mL (range 4.5–402.5) vs. median 11.6 ng/mL (range 1.2–87.1), respectively; P<0.001]; 2) patients with an unexplained fetal death and those associated with preeclampsia had a higher median plasma C5a concentration than normal pregnant women (P=0.002 and P<0.001, respectively); 3) no differences were observed in the maternal plasma concentrations of C3a and C4a among the study groups. Conclusions: Unexplained fetal death is associated with evidence of complement activation.

Objective: The complement system plays a central role in the first line of defense against invading pathogens, and its activation involves the release of potent pro-inflammatory mediators such as anaphylatoxins C3a, C4a and C5a. The aim of this study was to determine whether differences existed in maternal plasma anaphylatoxin concentrations between patients with term and preterm parturition. Study design: A cross-sectional study was designed to determine the plasma anaphylatoxin concentrations in 296 pregnant women in the following groups: 1) normal pregnancy between 20–36 6/7 weeks (n=64); 2) term not in labor (n=70); 3) term in labor (n=60); and 4) preterm labor with intact membranes (n=102). Women with preterm labor were classified into: a) term delivery (n=24); b) preterm delivery without intra-amniotic infection (IAI) (n=62); and c) preterm delivery with IAI (n=16). Concentrations of C3a, C4a and C5a were determined by ELISAs. Statistical analysis was conducted with non-parametric methods. Results: 1) The median plasma C5a concentration was lower in women at term in labor than in those not in labor (P<0.001). In contrast, there were no differences in plasma C3a and C4a concentrations between the two groups (P>0.05). 2) Among patients with preterm labor, those with IAI had a higher median plasma C5a concentration than those without IAI and those who delivered at term (post-hoc tests P<0.001 and P=0.01, respectively). When comparing the preterm labor subgroups with normal pregnancy, only women with preterm delivery and IAI had a median plasma C5a concentration higher than that of normal pregnant women (Kruskal-Wallis P<0.001, post hoc test P<0.001). There was no difference in the plasma C4a concentration among patients with preterm labor. The median plasma C3a concentration in patients with preterm labor with IAI was higher than in those without IAI (Kruskal-Wallis P=0.01, and post-hoc test P=0.005). There was no difference in the plasma C3a concentrations between women with preterm labor who delivered at term and those with preterm delivery, with or without IAI. In addition, no differences were observed in the median plasma C3a concentration between women with normal pregnancy and those in each of the preterm labor subgroups. Conclusions: The maternal plasma concentration of anaphylatoxin C5a is increased in women with preterm labor and IAI, but not in spontaneous labor at term.

Objective: The major tensile strength of fetal membranes is provided by their extracellular matrix (ECM) components. The transcription factor Ets-1 is a critical mediator of ECM remodelling. The purpose of this study was to examine whether Ets-1 is expressed in human fetal membranes and whether it is implicated in premature membrane rupture. Study design: Amniochorionic membranes from 52 women in the following categories were analyzed for Ets-1 expression: preterm and term premature rupture of membranes, preterm and term labor and delivery, and preterm and term cesarean sections without previous onset of labor. Ets-1 protein was localized with the use of immunohistochemistry. Ets-1 levels were determined with a histoscore. Results: Ets-1 protein was localized to the trophoblast as well as to the stromal layers. Ets-1 protein expression was up-regulated in the stroma of term and preterm prematurely ruptured membranes. Conclusion: Ets-1 is expressed in human fetal membranes and its expression is up-regulated with premature rupture of membranes, suggesting a role for Ets-1 in ECM remodelling of the membranes.

Objective: The following animal studies have been conducted to investigate whether recombinant human lactoferrin (rh-LF) has the same effect as bovine lactoferrin (b-LF) in the prevention of preterm delivery. Study Design: Female C3H/HeNCrj mice were pair-mated with male Crj:B6D2F1 mice. On day 15 of gestation, as a model of preterm delivery, a 50 μg/kg intraperitoneal injection of lipopolysaccharide (LPS) was administered twice with a 3-h interval between injections (2:00 and 5:00 PM). One hour prior to each LPS injection (1:00 and 4:00 PM), an intraperitoneal injection of saline, b-LF, or rh-LF (1 mg/body) was administered. In non-LPS-treated controls, an intraperitoneal injection of saline was administered 4 times (1:00, 2:00, 4:00 and 5:00 PM). Body weights and delivery times were recorded. To compare plasma levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) between experimental and other pregnant mice, prepared as above, were sacrificed 6 h after the second LPS injection, and then blood samples were obtained and analyzed. Results: Preterm delivery occurred (16.2±0.4 days of gestation) in all LPS-treated mice that were not administered LF. LF significantly prolonged gestation of LPS-treated mice: b-LF+LPS, 17.8±0.3 days; rh-LF+LPS, 18.0±0.8 days (P<0.05). LF (1 mg/body) significantly suppressed plasma IL-6 in LPS-treated mice:b-LF+LPS, 1060±154; rh-LF+ LPSF, 244±59; LPS without LF, 1628±115 pg/mL (P<0.05). As well, LF (1 mg/body) significantly suppressed plasma TNF-α in LPS-treated mice: b-LF+LPS, 88±36; rh-LF+LPS, 37±30; LPS without LF, 114±49 pg/mL (P<0.05). Conclusions: Rh-LF may prolong gestation in LPS-induced preterm delivery in mice, by suppressing LPS-induced plasma IL-6 and TNF-α augmentation.

Introduction and Objective: Cesarean section (CS) is the most common operation in obstetrics, with rising incidence in most countries. As a result of this operation late scar dehiscence may occur, which may lead to uterine rupture in a subsequent pregnancy. In this case series we have described sonographic detection of scar dehiscence after CS and feasibility of vaginal or combined laparoscopic and vaginal scar excision and uterine repair. Methods: Five consecutive patients underwent vaginal or laparoscopic assisted vaginal approach for repair of suspected scar dehiscence following CS, during a 5 year period. In all cases, transvaginal sonography detected suspicious features of scar dehiscence over the anterior uterine wall. Except of one, all patients had reported recurrent pelvic pain and/or irregular menstrual bleedings. Furthermore all patients planned for a further pregnancy. Results: Resection of the uterine defect and re-constitution of the uterine wall was successfully achieved in all five patients. There were no intra-operative complications and none of the patients required blood transfusion. The mean operation time was 117 min (27–192). Presence of scar tissue was confirmed on histology in all specimens. Four patients remained free of symptoms with no evidence of recurrent scar dehiscence on sonography over a median follow up of 30 months (3–46). One patient had an uneventful pregnancy 24 months after scar removal and was delivered by repeat CS at 39 weeks' gestation. Conclusion: Patients with a history of CS should undergo transvaginal sonography of the scar region in order to detect latent scar dehiscence in combination with uterine wall thinning prior to planning further pregnancy. In suspected cases, a combined laparoscopic – vaginal or vaginal approach can be employed to repair the defect.

We assessed ventricular volume with three-dimensional ultrasonography. The study group consisted of 54 infants admitted to the neonatal intensive care unit (NICU). Gestational age was 32.9±3.5 weeks and birth weight was 1774±623 g. To obtain images, the transducer was placed on the anterior fontanel. Sagittal sections were serially and automatically scanned from left to right. The angle of scanning was 60 degrees and five seconds were spent on e scanning. Two hundred fifty B-mode images were stored in the built-in computer for later retrieval. We chose the parasagittal sections from the midline to the lateral portion and traced manually an area of the lateral ventricle in each section at intervals of 1 mm. The built-in computer integrated them and measured the ventricular volume. The lateral ventricular size became larger during the first two weeks after birth. The left ventricle was larger than the right one. There was no correlation between lateral ventricular volume and birth weight. Our study shows the normal value of the lateral ventricular volume in neonates.

Objective To construct an ultrasonographic nomogram of the fetal gastric size with gestational age in normal singleton pregnancy. Patients and methods Out of 17 000 outpatient pregnant women who were admitted to our hospital, a total of 250 fetal measurements were randomly collected from routine ultrasonographic examinations performed in women with normal singleton pregnancies between 13 and 39 weeks of gestation without medical or obstetric complications. None of the fetuses had detectable fetal malformations. The ultrasound plane which provided the largest stomach area including the pylorus on a transverse and oblique section was used for definition and measurement of gastric longitudinal dimensions. The transverse section at the center of the gastric corpus was used for transverse and anteroposterior dimensions. Biparietal diameter, abdominal circumference were also measured. Results The fetal gastric longitudinal, anteroposterior and transverse dimensions were significantly correlated with gestational age (r values 0.74, 0.71, and 0.49, respectively). There was a significant correlation measurements between gastric size and AC. The correlation coefficents for gastric dimensions with gestational age was larger than those with AC (r=0.732, 0.702 and 0.489, respectively). The ratio of fetal gastric anteroposterior dimension to fetal AC was a constant parameter calculated as 1/3. Conclusion Fetal stomach dimensions in normal pregnancy correlate with gestational age and nomogram of fetal gastric development appears to be useful in assessment of normal fetal growth.

The possibility of a therapeutic role for cerebral hypothermia during or after resuscitation from perinatal asphyxia has been a long-standing focus of research. However, early studies had limited and contradictory results. It is now known that severe hypoxia-ischemia may not cause immediate cell death, but may precipitate a complex biochemical cascade leading to the delayed development of neuronal loss. These phases include a latent phase after reperfusion, with initial recovery of cerebral energy metabolism but EEG suppression, followed by a secondary phase characterized by accumulation of cytotoxins, seizures, cytotoxic edema, and failure of cerebral oxidative metabolism from 6 to 15 h post insult. Although many of the secondary processes can be injurious, they appear to be primarily epiphenomena of the ‘execution’ phase of cell death. This conceptual framework allows a better understanding of the experimental parameters that determine effective hypothermic neuroprotection, including the timing of initiation of cooling, its duration and the depth of cooling attained. Moderate cerebral hypothermia initiated in the latent phase, between one and as late as 6 h after reperfusion, and continued for a sufficient duration in relation to the severity of the cerebral injury, has been consistently associated with potent, long-lasting neuroprotection in both adult and perinatal species. The results of the first large multicentre randomized trial of head cooling for neonatal encephalopathy and previous phase I and II studies now strongly suggest that prolonged cerebral hypothermia is both generally safe – at least in an intensive care setting – and can improve intact survival up to 18 months of age. Both long-term followup studies and further large studies of whole body cooling are in progress.

Alveolar capillary dysplasia is a fatal disorder of the lung that requires lung biopsy for diagnosis. We reviewed the course of patients with alveolar capillary dysplasia following implementation of an early lung biopsy strategy between 1997–2002. We performed immunohisto-chemical studies on all tissue specimens. We diagnosed 7 cases of alveolar capillary dysplasia. We diagnosed 6/7 cases of alveolar capillary dysplasia pre-mortem by early lung biopsy. Median time between admission and lung biopsy was 6.5 days. All patients survived lung biopsy but died following withdrawal of active therapy after confirmation of the tissue diagnosis. In 1 patient we demonstrated histological findings of alveolar capillary dysplasia and congenital acinar dysplasia. Two patients were first cousins. One patient underwent pulmonary angiography with rapid filling of the pulmonary veins before passage of contrast through the capillary bed. Five patients were supported with extracorporeal membrane oxygenation and 2/5 patients survived decannulation. During the same period 8 patients required ECMO for acute hypoxic respiratory failure. Four out of 8 were diagnosed with alveolar capillary dysplasia. Conclusions : Early lung biopsy was performed with low risk and high diagnostic yield for alveolar capillary dysplasia. Alveolar capillary dysplasia occurs frequently in neonates who require ECMO support for refractory pulmonary hypertension. We have added an additional familial case and suggest a novel angiographic finding.

Aims. To follow the development of children born with myelomeningocoele. Methods. We followed 54 infants born with myelomeningocele between 1991 and 2001 in the Obstetrical Department of the Medical University of Gdansk, Poland. Results. The mortality rate for live births was 40.8%. 13.0% of the children were stillborn and 5.5% were lost for observation. Late diagnosis, a high localization of the lesion, the presence of other malformations, and low birth weight increased the risk of death. Diagnosis was most commonly made in the 31–35 th  week of pregnancy. For 18.5% of the subjects, the diagnosis was postnatal. There was no correlation between the time and mode of delivery and mental development. Only some of the children were able to walk, to use braces, or use a wheelchair. Most of the children had poor bladder and bowel control. We found a correlation between these dysfunctions and the level of myelomeningocele. Conclusions. Myelomeningocoele is associated with high rates of mortality and severe psychomotoric retardation. The localization of the lesion has an impact on survival rate and sphincter control. Mental development depends on neonatal condition after delivery. Mode of delivery does not influence the child's further development.

Anomalies occur with a greater frequency in twin gestations. Due to its multifactorial inheritance, twins are usually discordant for encephalocele. We present a case of monoamniotic twins concordant for occipital encephalocele and discordant for lung and cord anomalies. Ultrasonographic examination at 17 weeks' gestation revealed occipital encephalocele in both fetuses. The maternal serum level of alpha-fetoprotein was increased. Fetal autopsy revealed occipital encepaholocele in both twins and right pulmonary hypoplasia and one umbilical artery in one sibling. Monoamniotic twins concordant for encephalocele occur with extreme rarity. To the best of our knowledge, monoamniotic twins concordant for this neural tube defect have not been previously reported.

An asphyxiated infant with severe hypoxic-ischemic encephalopathy was treated by brain hypothermia using extracorporeal membrane oxygenation (ECMO). The brain hypothermia using ECMO maintained cardiopulmonary functions and stabilized brain temperatures by stably supply of the cooled blood to the brain. Moreover, we measured the levels of glucose, lactate, ionized calcium and glutamate in plasma. The comparison between these levels in the artery and in the cephalic vein, suggests that glucose, lactate, ionized calcium and glutamate might be used as markers of the effects of hypothermia therapy.

Cytomegalovirus (CMV) is the most common cause of congenital infection in humans. Some congenitally infected infants will develop sequelae later in life, especially sensorineural hearing loss (SNHL) and mental retardation. There is no generally accepted antiviral therapy for the treatment of symptomatic congenital CMV infections yet. We present a neonate with symptomatic congenital CMV infection, who was treated with intravenous (iv) ganciclovir (GCV) during 18 days and subsequently with oral valganciclovir (VGCV) for 5.5 months, in an attempt to prevent development of SNHL. GCV was given intravenously 10 mg/kg/day in two doses and VGCV doses ranged from 280–850 mg/m 2 bidaily (bid). Our experience shows that it is not possible to give a fixed dosing regime for VGCV in neonates and that continuous adaptation of dose is necessary to achieve stable target levels of GCV and to keep the viral load in urine at undetectable level. At 18 months of age no hearing deterioration has occurred. While the current findings are encouraging, the limitations of a single case report with a relatively short follow-up emphasizes the need for further prospective randomized studies to evaluate pharmacokinetics, efficacy and safety of VGCV therapy in neonates with congenital CMV infection.