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Can obstetric care provide further improvement in the outcome of preterm infants?

Reducing the incidence of cerebral damage in preterm infants has become a major objective of perinatal medicine. Recent studies have shown that intrapartum hypoxia is implicated in only 10% of cases, whereas prenatal factors are significantly linked with such damage. The main risk factors associated with cerebral palsy are preterm birth, multiple pregnancy, intrauterine infection, serious hypoxaemic and haemodynamic disorders and, possibly, thrombophilic disorders. Recent progress in recognition of the pathogenesis of cerebral white matter damage has underlined the roles of cytokines, including interleukins 1 and 6 and tumour necrosis factor alpha (TNFalpha), and of a massive release of glutamate, which leads to the excitotoxic cascade. Three measures have had demonstrable benefits in improving neonatal outcome in preterm infants: a policy of prenatal transfers to tertiary level care units, antenatal corticosteroid therapy, and administration of antibiotics to women with preterm premature rupture of membranes. The influence of tocolysis is usually considered to be relatively minor, but further studies in very preterm pregnancies may be required. The recent development of tocolytics without major adverse effects will probably facilitate such studies. The mode of delivery of early preterm infants is another important area of controversy. Recent studies have suggested that a policy of elective caesarean section in PPROM and in the case of breech presentation of fetuses weighing less than 1000-1500 g would be beneficial. Lastly, in vitro and animal studies have shown that several pharmacological agents can prevent white matter disease by interacting with cytokine and the excitotoxic cascade. This will probably constitute an important area of research in the future.

Birth Injuries↗

Predictive power of maternal serum and amniotic fluid CRP and PAPP-A concentrations at the time of genetic amniocentesis for the preterm delivery.

OBJECTIVE: To investigate whether maternal serum and amniotic fluid CRP and PAPP-A concentrations at the time of genetic amniocentesis are markers of preterm delivery. STUDY DESIGN: One hundred and forty-one pregnant women were included in this prospective study. Amniotic fluid and maternal serum CRP and PAPP-A concentrations were determined by using commercially available kits. Receiver-operating characteristic (ROC) analysis was performed to determine the efficacy of maternal serum and amniotic fluid CRP and PAPP-A levels in predicting women with preterm delivery. RESULTS: The prevalence of spontaneous preterm delivery before 37 weeks of gestation was 9.9%. ROC analysis revealed that amniotic fluid CRP level was the only parameter, which had a significant power in the prediction of preterm delivery. The optimum cut-off level was 0.65 mg/L. The sensitivity and specificity were 92.9% and 78.7%, respectively. CONCLUSION: The amniotic fluid CRP level has a high sensitivity and specificity in the prediction of preterm delivery and this may be helpful in predicting preterm delivery during genetic amniocentesis.

Adult↗

Preterm birth and low birth weight after assisted reproductive technology-related pregnancy in Australia between 1996 and 2000.

OBJECTIVE: To describe patterns of preterm birth and low birth weight (LBW) for infants born after assisted reproductive technology (ART) and determine whether these were associated with maternal or treatment characteristics. DESIGN: Retrospective cohort study of national population data of infants conceived through ART. SETTING: Australian birth records from 1996 to 2000. PATIENT(S): Eighteen thousand, four hundred twenty-nine liveborn and stillborn infants conceived through ART. INTERVENTION(S): In vitro fertilization, intracytoplasmic sperm injection, and gamete intrafallopian transfer. MAIN OUTCOME MEASURE(S): Preterm birth and LBW. RESULT(S): Preterm birth and LBW were more common among singletons and twins conceived with IVF and born to nulliparous mothers. Preterm birth and LBW were, respectively, 1.3 times and 1.5 times more likely to occur among singletons conceived by transfer of fresh embryos, compared with transfer of frozen embryos. Preterm birth and LBW was more common among couples who had female-factor infertility compared with male-factor infertility. CONCLUSION(S): The transfer of fresh embryos and female-factor infertility were independently associated with preterm birth and LBW for both singletons and twins after ART.

Adult↗

[Ultrasonographic measurement of cervical length in twin pregnancies with preterm labor: comparison with singleton pregnancies].

OBJECTIVE: Our purpose was to assess the utility of ultrasonographic measurement of cervical length for predicting preterm delivery in pregnant women with twin pregnancy and preterm labor. PATIENTS AND METHOD: Prospective study in 192 singleton and 66 twin pregnancies with preterm labor before 34 weeks. Vaginal sonography for measurement of cervical length, and screening for fetal fibronectin in vaginal smears were performed at admission. The incidence of delivery before 34 weeks was compared with cervical length and the presence of fetal fibronectin. RESULTS: In singleton pregnancies, delivery before 34 weeks was significantly more frequent in women with a cervical length <30 mm (26.6 vs. 2.0%; P = 0.0004), or presence of fetal fibronectin (27.5 vs. 6.0%; P = 0.001). The corresponding negative predictive values (NPV) were 98% and 94%, respectively. In twin pregnancies, receiver characteristic curve analysis showed that a cervical length of 20 mm had the highest diagnostic performance in predicting preterm delivery. The corresponding NPV was 63%. In this group, delivery before 34 weeks showed no significant difference in women with a cervical length < 30 mm (43.7 vs. 38.8%), cervical length < 20 mm (52.0 vs. 36.6%, P = 0.219), or presence of fetal fibronectin (47.6 vs. 21.7%, P = 0.0705). DISCUSSION AND CONCLUSION: Ultrasonographic measurement of cervical length does not predict preterm delivery in twin pregnancies with preterm labor.

Adult↗

Joint attention in term and preterm infants at 12 months corrected age: the significance of gender and intervention based on a randomized controlled trial.

This study tested the effects of optimized neonatal mother-infant transactions on joint attention performance at 12 months. Surviving infants <2000g from a geographically defined area were randomly assigned to a preterm intervention (n=71) or preterm control group (n=69). Comparisons were made between preterm groups, secondary with a term group (n=75). Joint attention was measured using the Early Social Communication Scales. Preterm intervention infants scored significantly higher than preterm control infants on elements Initiating Joint Attention (p<0.05), Initiating Object Requests (p<0.05), and Responding to Social Interaction (p<0.0005). Intervention was not associated with performance on elements Responding to Joint Attention, or on Responding to Requests. ELBW infants scored significantly lower than VLBW and LBW infants on imperative functions. Girls outperformed boys on all communication elements. An intervention implemented during the neonatal period can be of advantage for certain aspects of joint attention performance in preterm infants.

Adult↗

Preterm delivery and asthma: a systematic review and meta-analysis.

BACKGROUND: Accumulating evidence suggests that reduced duration of pregnancy predicts increased risk of asthma, but the studies published have been inconsistent. OBJECTIVE: We sought to synthesize the evidence on the relation between preterm delivery and the risk of asthma later in life and to assess differences between the studies as potential sources for heterogeneity of the results. METHODS: We conducted a MEDLINE search (until the end of May 2005). The outcome was asthma. The determinant of interest was preterm delivery defined as a gestational age of less than 37 weeks. RESULTS: We identified 19 articles that provided estimates for the meta-analysis. The summary effect estimates for asthma (fixed-effects odds ratio, 1.074 [95% CI, 1.072-1.075]; heterogeneity P = .000; random-effects odds ratio, 1.366 [95% CI, 1.303-1.432]) showed an increased risk in relation to preterm delivery, with substantial heterogeneity between study-specific estimates. The effect of preterm delivery on asthma was stronger in cross-sectional studies; studies with broad outcome criteria, a small sample size, and a younger study population; and studies conducted in English-speaking populations, outside Europe, and published more recently. In metaregression, adjusting for other determinants, the effect estimate was significantly associated only with the mean age of the study population. CONCLUSIONS: The weight of evidence shows that preterm babies have an increased risk of asthma compared with term babies. CLINICAL IMPLICATIONS: Recognition of prematurity as a determinant of asthma emphasizes the importance of active treatment of physiologic airflow obstruction and a need for special preventive measures against known environmental determinants of asthma in preterm babies.

Asthma↗

Vagal activity, gastric motility, and weight gain in massaged preterm neonates.

OBJECTIVE: Multiple studies have documented an increase in weight gain after 5 to 10 days of massage therapy for preterm neonates. The massaged preterm neonates did not consume more calories than the control neonates. One potential mechanism for these effects might involve massage-induced increases in vagal activity, which in turn may lead to increased gastric motility and thereby weight gain. STUDY DESIGN: The present randomized study explored this potential underlying mechanism by assessing gastric motility and sympathetic and parasympathetic nervous system activity in response to massage therapy (moderate pressure) versus sham massage (light pressure) and control conditions in a group of preterm neonates. RESULTS: Compared with preterm neonates receiving sham massage, preterm neonates receiving massage therapy exhibited greater weight gain and increased vagal tone and gastric motility during and immediately after treatment. Gastric motility and vagal tone during massage therapy were significantly related to weight gain. CONCLUSION: The weight gain experienced by preterm neonates receiving moderate-pressure massage therapy may be mediated by increased vagal activity and gastric motility.

Analysis of Variance↗

Preterm delivery induced by LPS in syngeneically impregnated BALB/c and NOD/SCID mice.

Strategies of lipopolysaccharide (LPS) stimulation with or without previous toll-like receptor 4 (TLR4) blocking were pursued to investigate the mechanism of LPS-induced preterm delivery in syngeneically impregnated BALB/c and non-obese diabetic (NOD)/LtSz-scid/scid (NOD/SCID [severe combined immunodeficiency] for short) mice. The LPS-stimulated mice were killed at the beginning of preterm labor and pooled placentas were collected in each mouse. Cell surface expression of TLR4, CD80, and intracellular TNF-alpha in placenta CD45(+) cell population was determined by flow cytometry. It displayed that preterm delivery could be induced by LPS in BALB/c, while the NOD/SCID seemed to be resistant to LPS induction. TLR4 expression was not changed in either BALB/c or NOD/SCID mice upon LPS-stimulation, but the CD45(+)CD80(+) cell percentage was elevated in both groups. The CD45(+)TNF-alpha(+) cell percentage was increased merely in BALB/c after the stimulation, while no such trend was observed in NOD/SCID mice. In BALB/c, the effect of LPS on CD80 and TNF-alpha expression could be abrogated by previous TLR4 blocking, subsequently prevent LPS-induced preterm delivery. In another design, NK cell blocking was performed at earlier stage of gestation by injections of anti-asialo GM1 antiserum (ASGM1). It appeared that LPS-induced preterm delivery could be partially prevented by this blocking in BALB/c mice. Such data, together with the diversity of sensitivity to LPS induction observed in BALB/c and NOD/SCID mice, imply that LPS interacts with TLR4, triggers the mobilization of CD45(+)CD80(+) cells, results in elevated production of inflammatory cytokines, and finally results in preterm delivery. In addition, NK cells may be involved in the signaling cascade, and the lack of functional NK cells in the NOD/SCID may be why these mice appeared to be less sensitive to LPS-induced premature labor.

Animals↗

Predictive value of maternal serum and vaginal interleukin-6 levels in preterm labor.

OBJECTIVE: The aim of the current study was to evaluate the predictive value of maternal serum and vaginal interleukin 6 (IL-6) levels for preterm delivery before 37 gestational weeks in patients with preterm labor and to determine the probable relationship between IL-6 concentrations and delivery interval. METHODS: In this prospective study, maternal serum and vaginal IL-6 levels were measured in 40 patients with the diagnosis of preterm labor between the 28th and 36th gestational weeks (study group) and in 20 pregnant women between the same gestational weeks attending the antenatal clinic with no complaints (control group). The gestational age at the time of admission and delivery, as well as the delivery interval, were evaluated and compared with the concentration of IL-6 on admission. RESULTS: There were no significant relationships between maternal serum concentrations of IL-6 and preterm delivery. Vaginal IL-6 levels were significantly higher in the study group as compared with the control group (P < .001). The optimal cut-off value for vaginal IL-6 (172 pg/mL) gave a sensitivity level of 73.9% (95% confidence interval [CI], 67-82%) at a specificity of 100% (95% CI, 91-100%) with positive and negative predictive values of 94.1% and 83.7%, respectively. In the study group, the interval from collection to delivery was significantly shortened when the maternal vaginal IL-6 levels increased. CONCLUSION: The ease of measurement, feasibility, cost-effectiveness, and success of identifying pregnancies at risk for preterm labor with vaginal IL-6 make this a useful biochemical marker for preterm labor and delivery.

Adult↗

The promise of prostaglandins: have they fulfilled their potential as therapeutic targets for the delay of preterm birth?

OBJECTIVE: The elucidation some 30 years ago by Sir Mont Liggins that the activation of the hypothalamic-pituitary-adrenal-placental axis in fetal sheep led to elevated maternal prostaglandin (PG) concentrations and the initiation of labor provided hope that targeting PG synthesis or action would lead to effective tocolysis and lowering of the human preterm birth rate. This was the "promise of PGs." METHODS AND RESULTS: Although early trials showed that nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit PG H synthase (PGHS), delayed preterm birth by 48 hours, other trials revealed an association between NSAIDs and adverse fetal effects, including oligohydramnios, patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage, and persistent pulmonary hypertension of the newborn (PPHN). Hope was revived when studies in the mid 1990s demonstrated that much of the PGs synthesized by intrauterine tissues at preterm labor were derived from the inducible isoenzyme PGHS-2. Unfortunately, administration of specific PGHS-2 inhibitors led to the same adverse fetal effects displayed by the mixed PGHS-1 and -2 NSAIDs, causing interest in the promise of PGs to wane. This led to the development of new strategies for specific PG inhibition or antagonism. One of these is the application of a specific PGF2alpha receptor blocker, Theratechnologies (THG)113.31. THG113.31 decreases the in vitro contractile activity of mouse, sheep, and human myometrium in response to exogenous PGF2alpha, delays lipopolysaccharide (LPS)-induced preterm birth in mice, and lowers uterine electromyographic activity and delays preterm birth in sheep administered RU486. There have been no observable maternal or fetal side effects with its use. CONCLUSION: By developing new strategies based on other therapeutic targets, the promise of PGs may once again offer hope for delaying preterm birth.

Adult↗

Effect of stimulation and antagonism of interleukin-1 signaling on preterm delivery in mice.

OBJECTIVE: Transgenic mice that overexpress the interleukin-1 receptor antagonist (IL-1ra), an endogenous competitive inhibitor of interleukin-1 (IL-1) signaling, were used to test whether blockade of IL-1 can prevent bacterially induced preterm delivery in a validated murine model. These IL-1ra transgenic mice have been shown previously to be protected from lethal endotoxin shock. METHODS: In a series of four separate experiments, 201 female wild-type and transgenic mice on day 14.5 of a 19-20 day gestation underwent intrauterine injection with either 0.5-20 microg of recombinant human IL-1beta (rhIL-1beta) or 10(5)-10(8) heat-killed Escherichia coli organisms. Fetuses were either all wild-type, all transgenic, or of mixed genotype (see below). Preterm delivery and maternal survival rates were recorded. IL-1ra protein levels were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Intrauterine administration of IL-1beta induced preterm delivery in a dose-dependent manner and did not cause other adverse maternal effects. In bacterially inoculated mice, neither maternal nor fetal carriage of the IL-1ra overexpression transgene affected preterm delivery rates. Fetal carriage of the IL-1ra transgene did not up-regulate IL-1ra protein levels in maternal or fetal tissues. CONCLUSION: Although intrauterine IL-1 exposure is sufficient for induction of preterm delivery, it was not possible to prevent bacterially induced preterm birth using the IL-1ra transgene. This may be either because the timing or magnitude of IL-1ra up-regulation in transgenic mice was insufficient to block IL-1's interaction with its receptor, or because bacterially induced labor in this model does not depend on IL-1 signaling alone.

Animals↗

Elevated mid-trimester amniotic fluid ADAM-8 concentrations as a potential risk factor for preterm delivery.

OBJECTIVE: To determine during mid-trimester amniocentesis if elevated concentrations of ADAM-8 (A Disintegrin And Metalloprotease 8) and/or cortisol can recognize women at risk for spontaneous preterm delivery. METHODS: The study involved 312 women who underwent mid-trimester amniocentesis. Thirteen patients, who progressed to preterm delivery, were matched with 21 controls for age, parity, gestational age at amniocentesis, and year of amniocentesis. ADAM-8 and cortisol levels were measured by enzyme-linked immunosorbent assay and radioimmunoassay, respectively. RESULTS: ADAM-8 mean amniotic fluid concentrations were significantly higher in women with preterm delivery than in women delivering at term (mean 1213.9 [SE 96.7] pg/mL [range, 780 to 1854 pg/mL] vs mean 937.2 [SE 50.3] pg/mL [range, 486 to 1508 pg/mL], P < .02). Amniotic fluid ADAM-8 concentrations higher than 1149 pg/mL had the highest specificity and odds ratio (OR) in the identification of the women with increased risk for preterm delivery (sensitivity 61.5%; specificity 81.7%; OR, 9.6 [95% confidence interval (CI), 1.8 to 50.3]). Women with preterm delivery had suggestively higher amniotic fluid concentrations of cortisol (mean 1.3 [SE 0.2] microg/dL [range, 0.4 to 2.2 microg/dL]) than women delivering at term (mean 1.0 [SE 0.09] microg/dL [range, 0.6 to 1.7 microg/dL], P < .07). Furthermore, cortisol levels were positively correlated with ADAM-8 levels (Spearman's r = .418, P < .014). CONCLUSIONS: Elevated mid-trimester amniotic fluid ADAM-8 concentrations possibly are a risk factor for preterm delivery, particularly if ADAM-8 levels are greater than 1149 pg/mL. Potential intrauterine inflammation is also associated with suggestively increased amniotic fluid cortisol levels.

ADAM Proteins↗

n-6 and n-3 Long-chain polyunsaturated fatty acids in the erythrocyte membrane of Brazilian preterm and term neonates and their mothers at delivery.

Placental transfer of the long-chain polyunsaturated fatty acids (LCPUFA) arachidonic (AA) and docosahexaenoic (DHA) acids is selectively high to maintain accretion to fetal tissues, especially the brain. The objectives of the present study were to investigate the essential fatty acid (EFA) and LCPUFA status at birth of preterm and term Brazilian infants and their mothers, from a population of characteristically low intake of n-3 LCPUFA, and to evaluate the association between fetal and maternal status, by the determination of the fatty acid composition of the erythrocyte membrane. Blood samples from umbilical cord of preterm (26-36 weeks of gestation; n = 30) and term (37-42 weeks of gestation; n = 30) infants and the corresponding maternal venous blood were collected at delivery. The LCPUFA composition of the erythrocyte membrane and DHA status were similar for mothers of preterm and term infants. Neonatal AA was higher (P < 0.01) whereas its precursor 18:2n-6 was lower (P < 0.01) than maternal levels, as expected. There was no difference in LCPUFA erythrocyte composition between preterm and term infants, except for DHA. Term infants presented a worse DHA status than preterm infants (P < 0.01) and than their mothers (P < 0.01) at delivery. There was a negative correlation of neonatal DHA with maternal AA and a positive correlation between neonatal AA and maternal AA and 18:2n-6 only at term. These results suggest that the persistent low DHA maternal status, together with the comparatively better AA and 18:2n-6 status, might have affected maternal-fetal transfer of DHA when gestation was completed up to term, and possibly contributed to the worse DHA status of term neonates compared with the preterm neonates.

Brazil↗

The genetic contribution towards preterm delivery.

Indirect evidence supports a possible genetic predisposition towards preterm birth. The recurrence of spontaneous preterm delivery in individual women, families and ethnic groups suggests a long-acting aetiology, consistent with a genetic factor. Genetic contributions from both mother and fetus probably play a role in determining gestational length. Preliminary genetic association studies implicate gene variants of tumor necrosis factor-alpha (TNF-alpha) in preterm birth. Further understanding of a genetic predisposition begins with investigation of the pathogenesis of preterm delivery. Technological advances in the study of the human genome (genomics) and protein complement (proteomics) will allow identification of novel genes and proteins involved in preterm delivery. Insight into the complex gene regulation and protein production in preterm delivery may contribute to an understanding of a genetic basis. A discovered genetic factor may lead to medical breakthroughs and reductions in prematurity, neonatal morbidity and mortality.

Adult↗

Animal models of preterm birth.

Preterm birth continues to pose a significant clinical dilemma and contributes to both acute and long-term neonatal morbidity. Despite efforts, the incidence of preterm birth has not decreased, partly because of our lack of understanding of the mechanisms that trigger parturition. Animal models are essential research tools for investigating the pathways that promote preterm parturition and for testing therapeutic interventions. Growing evidence correlates infection or inflammation with preterm birth. Consequently, many investigators have created animal models that reflect these findings. Current models of preterm parturition include diverse species, varying means of inducing an inflammatory or infectious state, and different routes of administration. Although each of these models can advance our knowledge, it is important to understand their advantages, disadvantages and unique characteristics. An understanding of such models will hopefully promote continued research that will ultimately lead to a decrease in preterm birth and an improvement in neonatal outcome.

Amnion↗

Immunogenicity and induction of immunological memory of the heptavalent pneumococcal conjugate vaccine in preterm UK infants.

Data on the immunogenicity and memory induction of pneumococcal conjugate vaccines in very preterm infants is limited. We vaccinated 69 full term and 68 preterm infants (median gestational age (GA) 30 weeks) with a 7-valent pneumococcal conjugate vaccine (PCV7) at 2/3/4 months of age, followed by a plain polysaccharide booster at 12 months of age. IgG-GMC (ELISA) was significantly lower in preterm infants to six vaccine serotypes (ST) at 2 months and 5 months of age, to five ST at 12 months of age and to three ST at 13 months of age. A significantly lower proportion of preterm infants achieved IgG levels>or=0.35 microg/ml to ST 4, 6B and 9V at 5 months and to ST 4, 6B, 18C, 19F and 23F at 12 months of age. Fold rises following the polysaccharide booster were comparable to those of term infants. At least 93% of both cohorts achieved IgG>or=0.35 microg/ml to all STs following booster vaccination. Pneumococcal conjugate vaccine at an accelerated schedule of 2/3/4 months of age is likely to provide protection against pneumococcal disease for preterm infants. Antibody concentrations wane over the first year of life in both preterm and term infants and booster vaccination is therefore likely to be important.

Antibodies, Bacterial↗

A systematic review and meta-analysis of prospective studies on the association between maternal cigarette smoking and preterm delivery.

We have attempted to quantify the most up-to-date estimate of the association between cigarette smoking by the mother and preterm delivery. Studies were selected for inclusion in this review if they were prospective, reported data stratified across at least two levels of maternal smoking, and defined preterm delivery on the basis of gestational age. In a meta-analysis we combined results from multiple studies that reported on preterm delivery and maternal smoking during pregnancy. Pooled odds ratios were computed for various strata of smoking intensity with the Mantel-Haenszel fixed-effects model. Twenty studies met all inclusion criteria and were included in meta-analysis. The pooled point estimate from 20 prospective studies on any maternal smoking versus no maternal smoking was 1.27 (95% confidence interval, 1.21-1.33). Subgroup analyses stratifying maternal smoking on number of cigarettes per day suggest a dose-response relationship at low to moderate levels of smoking, which was not further increased at high levels of smoking. A nonsignificant level of publication bias appears to exist in the smoking-preterm delivery literature. Cigarette smoking is a preventable risk factor that is associated with preterm delivery. Consistent results across many study populations and research designs and evidence of a dose-response relationship support its causal role in preterm delivery.

Case-Control Studies↗

Elevated maternal plasma corticotropin-releasing hormone levels in pregnancies complicated by preterm labor.

OBJECTIVES: We investigated whether maternal plasma levels of the placental hormone corticotropin-releasing hormone are elevated in pregnancies complicated by preterm labor. STUDY DESIGN: Mean maternal corticotropin-releasing hormone levels were studied in women who met specific criteria for preterm labor and in women with normal pregnancies. Levels were also compared in the latent and active phases during term labor. RESULTS: In pregnancies complicated by preterm labor, maternal corticotropin-releasing hormone levels were higher than in normal pregnancies; this elevation occurred before labor was diagnosed clinically (p less than 0.05). When preterm labor was associated with infection, the mean levels were not elevated. Mean plasma levels were similar in latent and active phases during labor at term. CONCLUSION: Maternal plasma corticotropin-releasing hormone levels are elevated in association with preterm labor. This elevation does not appear to be due to labor itself and may reflect an early activation of the placenta before the onset of preterm labor.

Corticotropin-Releasing Hormone↗