Jasper V. Been

Histologic chorioamnionitis, fetal involvement, and antenatal steroids: effects on neonatal outcome in preterm infants

OBJECTIVE The objective of the study was to study the effects of histologic chorioamnionitis (HC) with or without fetal involvement and antenatal steroid (AS) exposure on neonatal outcome in a prospective cohort of preterm infants. STUDY DESIGN The clinical characteristics and placental histology were prospectively collected in 301 infants born at a gestational age 32.0 weeks or less in the Erasmus University Medical Center. RESULTS In univariable analyses, HC without fetal involvement (n=53) was associated with decreased severe respiratory distress syndrome (RDS) (11% vs 28%; P<.05), whereas HC with fetal involvement infants (n=68) had more necrotizing enterocolitis (9% vs 2%; P<.05), intraventricular hemorrhage (IVH) (25% vs 12%; P<.05), and neonatal mortality (19% vs 9%; P<.05). In HC without fetal involvement infants, AS reduced the incidences of RDS (43% vs 85%; P<.05) and IVH (5% vs 39%; P<.01). In multivariable analyses, HC without fetal involvement was associated with decreased severe RDS (odds ratio, 0.22; 95% confidence interval, 0.05-0.93; P<.05) and increased early-onset sepsis (odds ratio, 2.22; 95% confidence interval, 1.02-4.83; P<.05). CONCLUSION In a prospective cohort of preterm infants, multivariable analyses reveal only a modest association between histologic chorioamnionitis and neonatal outcome.

Chorioamnionitis Alters the Response to Surfactant in Preterm Infants

OBJECTIVE To study the association between antenatal exposure to chorioamnionitis and the neonatal response to surfactant. STUDY DESIGN Prospective observational cohort of 301 preterm infants of gestational age < or = 32.0 weeks, 146 of whom received surfactant according to standardized criteria. Fraction of inspired oxygen (FiO(2)) requirement (using analysis of variance) and time to extubation (using Kaplan-Meier and Cox regression analyses) were compared between groups based on the presence of histological chorioamnionitis (HC) with or without fetal involvement (HC-, n = 88; HC + F-, n = 25; HC + F+, n = 33) and between infants who developed bronchopulmonary dysplasia (BPD) or died (n = 57) and BPD-free survivors (n = 89). Multiple logistic regression was performed to investigate the association between HC and BPD. RESULTS Compared with HC- infants, HC + F+ infants had significantly greater FiO(2) requirement and prolonged time to extubation postsurfactant, not accounted for by differences in gestational age and birth weight. Infants with BPD/death had a strikingly similar pattern of increased FiO(2) requirement postsurfactant. Moreover, in infants who received surfactant, HC + F+ status was associated with increased risk for BPD (odds ratio [OR] = 3.40; 95% confidence interval [CI] = 1.02-11.3; P = .047) and for BPD/death (OR = 2.72; 95% CI = 1.00-7.42; P = .049). CONCLUSIONS An impaired surfactant response was observed in preterm infants with severe chorioamnionitis and may be involved in the association between chorioamnionitis, mechanical ventilation, and the development of BPD.

Chorioamnionitis as a risk factor for necrotizing enterocolitis: a systematic review and meta-analysis.

OBJECTIVE To accumulate available evidence regarding the association between antenatal inflammation and necrotizing enterocolitis (NEC). STUDY DESIGN A systematic literature search was performed using Medline, Embase, Cochrane Library, ISI Web of Knowledge, and reference hand searches. Human studies published in English that reported associations between chorioamnionitis or other indicators of antenatal inflammation and NEC were eligible. Relevant associations were extracted and reported. Studies reporting associations between histological chorioamnionitis (HC) and NEC, HC with fetal involvement and NEC, and clinical chorioamnionitis and NEC were pooled in separate meta-analyses. RESULTS A total of 33 relevant studies were identified. Clinical chorioamnionitis was significantly associated with NEC (12 studies; n = 22 601; OR, 1.24; 95% CI, 1.01-1.52; P = .04; I(2) = 12%), but the association between HC and NEC was not statistically significant (13 studies; n = 5889; OR, 1.39; 95% CI, 0.95-2.04; P = .09; I(2) = 49%). However, HC with fetal involvement was highly associated with NEC (3 studies; n = 1640; OR, 3.29; 95% CI, 1.87-5.78; P ≤ .0001; I(2) = 10%). Selection based on study quality did not affect the results. No indications of publication bias were apparent. Multivariate analyses in single studies generally attenuated the reported associations. Several associations between other markers of antenatal inflammation and NEC are reported. CONCLUSION Currently available evidence supports a role for antenatal inflammation in NEC pathophysiology. This finding emphasizes the need to further study the underlying mechanisms and evaluate potential interventions to improve postnatal intestinal outcomes.

Thymic changes after chorioamnionitis induced by intraamniotic lipopolysaccharide in fetal sheep

OBJECTIVE Regulatory T lymphocytes mediate homeostasis of the immune system and differentiate under the control of the transcription factor FoxP3 in the fetal thymus. We asked whether fetal inflammation caused by chorioamnionitis would modulate thymus development. STUDY DESIGN Fetal sheep were exposed to an intraamniotic injection of 10 mg lipopolysaccharide at 5 hours, 1 day, 2 days, or 5 days before delivery at 123 gestation days. Cord blood lymphocytes, plasma cortisol, and thymus weight were measured. Glucocorticoid receptor-, activated caspase-3-, Ki-67-, proliferating cell nuclear antigen-, nuclear factor-kappaB-, and FoxP3-positive cells were immunohistochemically evaluated in thymus. RESULTS Intraamniotic lipopolysaccharide exposure decreased the number of circulating lymphocytes by 40% after 1 day. Thymus-to-body weight ratios were reduced in all lipopolysaccharide groups by a maximum of 40% at 5 days. Lipopolysaccharide exposure modestly increased plasma cortisol concentration, increased nuclear factor-kappaB immunostaining in fetal thymus and reduced the number of FoxP3-positive cells by 40% at 1 day. CONCLUSION Intraamniotic exposure to lipopolysaccharide induced thymic changes and influenced thymic FoxP3 expression.

Epidemiology of pyridoxine-dependent seizures in The Netherlands

Background: Pyridoxine dependent epilepsy is a rare cause of seizures in childhood. The diagnosis is made on clinical criteria, that in many cases are never met. Therefore, epidemiological data on pyridoxine dependency are scarce. Aims: To study the epidemiology of pyridoxine dependent epilepsy in the Netherlands, and to determine whether the diagnosis is based on the appropriate criteria. Methods: Nationwide all departments of paediatrics (n = 113) and of paediatric or neonatal neurology (n = 17) were asked to report cases of pyridoxine dependent seizures. Birth incidences were calculated using national data on live births from 1991 to 2003. Results: Response was received from 67% of paediatric departments, including all university hospitals and 94% of child neurology departments. Thirteen patients were reported. Four definite (31%), three probable (23%), and four possible cases (31%) were identified. Two cases (15%) did not meet criteria for either of these groups. The birth incidence was 1:396 000 for definite and probable cases and 1:252 000 when possible cases are included. Conclusions: Thus far, epidemiological data on pyridoxine dependent seizures were only available from the UK and Ireland. A higher incidence was found in the Netherlands, in accordance with earlier suggestions of a regional difference. The study shows that the diagnosis is often made without performance of a formal trial of withdrawal. The importance of confirming the diagnosis, concerning the consequences as for individual prognosis, the potential side effects of prolonged pyridoxine substitution, and the possibility of treating the mother in case of future pregnancies are emphasised.

Placental pathology and long-term neurodevelopment of very preterm infants

OBJECTIVE The objective of the study was to compare neonatal morbidity and long-term neurodevelopmental outcome between very preterm infants with placental underperfusion and very preterm infants with histological chorioamnionitis. STUDY DESIGN We measured the mental and motor development at age 2 and 7 years in 51 very preterm infants with placental underperfusion and 21 very preterm infants with histological chorioamnionitis. RESULTS At 2 years, very preterm infants with placental underperfusion had poorer mental development than very preterm infants with histological chorioamnionitis (mean [SD] 90.8 [18.3] vs 104.1 [17.2], adjusted d = 1.12, P = .001). Motor development was not different between both groups (92.8 [17.2] vs 96.8 [8.7], adjusted d = 0.52, P = .12). At 7 years, large, although nonsignificant, effects were found for better mental and motor development and fewer behavioral problems in infants with histological chorioamnionitis. CONCLUSION Placental pathology contributes to variance in mental development at 2 years and should be taken into account when evaluating neurodevelopmental outcome of very preterm infants.

Intravenous lipopolysaccharide-induced pulmonary maturation and structural changes in fetal sheep

BACKGROUND Antenatal pulmonary inflammation is associated with reduced risk for respiratory distress syndrome but with an increased risk for bronchopulmonary dysplasia (BPD) with impaired alveogenesis. OBJECTIVE We hypothesized that fetal systemic inflammation induced by intravenous (IV) lipopolysaccharide (LPS) would affect lung development in utero. STUDY DESIGN Twenty-one fetal sheep were instrumented (107 days gestational age). Control fetuses received saline (N = 12) and 9 in the study group received 100 ng of LPS IV 3 days after surgery. Animals were assessed for lung maturation and structure after 3 (N = 5) and 7 (N = 4) days. RESULTS Interleukin-6 concentration increased in the bronchoalveolar lavage more than 40-fold 3 days after LPS IV. Processing of pro-surfactant protein (SP)-B to mature SP-B and increased SP-B concentrations were shown 7 days after LPS IV. Deposition of elastin fibers at sites of septation was disturbed within 3 days after LPS IV. CONCLUSION Lung maturation and disturbed lung structure occurred after short-term exposure to fetal inflammation and suggests new targeted therapies for BPD.

Pulmonary vascular endothelial growth factor expression and disaturated phospholipid content in a chicken model of hypoxia-induced fetal growth restriction.

Background: Prenatal hypoxia is an important cause of intrauterine growth retardation that affects fetal lung maturation, although previous studies have rendered conflicting results. The fetal chicken model allows the study of the isolated effects of hypoxia during development. Objectives: We hypothesized that prenatal hypoxia would differentially affect surfactant synthesis, depending on timing and duration of hypoxia. Pulmonary vascular endothelial growth factor (VEGF) expression was analyzed as a possible link between oxygen sensing and surfactant production. Methods: Fertilized White Leghorn eggs were incubated in normoxia, hyperoxia (60% O2) from day 15 or hypoxia (15% O2) from either day 6 or day 15 of incubation. Whole lung disaturated phospholipids (DSPL) and mRNA expression of VEGF isoforms were quantified at day 16 and 19. Results: Lung DSPL content increased approximately threefold between day 16 and 19 in control animals. Both hypoxia and hyperoxia from day 15 significantly increased DSPL content at day 19 versus control (103 ± 22 and 116 ± 18 vs. 81 ± 15 µg/mg protein, p < 0.01 and p < 0.001, respectively), while long-term hypoxia tended to decrease DSPL content (65 ± 17 µg/mg protein, p = 0.056). No differences in DSPL content were observed at day 16. Short-term hypoxia transiently up-regulated VEGF146 1.5-fold at day 16 (p < 0.05). A similar trend was observed for VEGF122 (p = 0.058) and VEGF190 (p = 0.08), while no differences were present at day 19. Conclusions: Both prenatal hypoxia and hyperoxia induced during critical windows of lung development differentially modulate surfactant synthesis. Our data support the concept that fetal oxygen tension is a key signal in the regulation of the surfactant system.

Porphyromonas gingivalis within placental villous mesenchyme and umbilical cord stroma is associated with adverse pregnancy outcome

Intrauterine presence of Porphyromonas gingivalis (Pg), a common oral pathobiont, is implicated in preterm birth. Our aim was to determine if the location of Pg within placental and/or umbilical cord sections was associated with a specific delivery diagnosis at preterm delivery (histologic chorioamnionitis, chorioamnionitis with funisitis, preeclampsia, and preeclampsia with HELLP-syndrome, small for gestational age). The prevalence and location of Pg within archived placental and umbilical cord specimens from preterm (25 to 32 weeks gestation) and term control cohorts were evaluated by immunofluorescent histology. Detection of Pg was performed blinded to pregnancy characteristics. Multivariate analyses were performed to evaluate independent effects of gestational age, being small for gestational age, specific preterm delivery diagnosis, antenatal steroids, and delivery mode, on the odds of having Pg in the preterm tissue. Within the preterm cohort, 49 of 97 (51%) placentas and 40 of 97 (41%) umbilical cord specimens were positive for Pg. Pg within the placenta was significantly associated with shorter gestation lengths (OR 0.63 (95%CI: 0.48–0.85; p = 0.002) per week) and delivery via caesarean section (OR 4.02 (95%CI: 1.15–14.04; p = 0.03), but not with histological chorioamnionitis or preeclampsia. However, the presence of Pg in the umbilical cord was significantly associated with preeclampsia: OR 6.73 (95%CI: 1.31–36.67; p = 0.02). In the term cohort, 2 of 35 (6%) placentas and no umbilical cord term specimens were positive for Pg. The location of Pg within the placenta was different between preterm and term groups in that Pg within the villous mesenchyme was only detected in the preterm cohort, whereas Pg associated with syncytiotrophoblasts was found in both preterm and term placentas. Taken together, our results suggest that the presence of Pg within the villous stroma or umbilical cord may be an important determinant in Pg-associated adverse pregnancy outcomes.

Early postnatal blood pressure in preterm infants: effects of chorioamnionitis and timing of antenatal steroids.

Previous studies suggest postnatal blood pressure in preterm infants to be decreased by chorioamnionitis and increased by antenatal steroids (AS). We examined the adjusted effects of both antenatal modulators on postnatal blood pressure (BP), with separate effects reported for histologic chorioamnionitis with or without fetal involvement and timing of AS. General characteristics, BP, and heart rate values during the first 72 h after birth were obtained from 271 infants with gestational age ≤32.0 wk. In unadjusted analyses, chorioamnionitis was associated with lower BP, most prominently so in infants with fetal involvement, without an effect on hypotension incidence. AS increased BP and decreased the incidence of hypotension when administered within 7 d before birth. In a multivariable mixed model analysis, the AS effect remained significant, whereas chorioamnionitis was not independently predictive of postnatal BP. Other variables associated with increased postnatal BP were gestational age and umbilical artery pH, whereas hemolysis, elevated liver enzymes, low platelets syndrome was associated with decreased BP. In conclusion, AS seem to increase postnatal BP and decrease hypotension in preterm infants when given within 7 d before birth. Conversely, chorioamnionitis did not significantly affect postnatal BP after multivariable adjustment.