Terms Of Neonatal Outcomes Research Articles

37 A Specified Type of Apgar - Results of the International Test-Apgar Study

Background: There is considerable variation in assigning Apgar scores. Definitions are required to apply Apgar score under clinical conditions such as preterm delivery or resuscitation [Rudiger et al. ActaPaed'09:98;1433-36]. American Academy of Pediatrics suggested an additional form for resuscitated infants [Ped'06:117;1444-47], however, its predictive value was not tested until now. Aim: Test the prognostic value of a specified Apgar score and the AAP-suggestion to predict short term neonatal outcome of preterm infants. Methods: Comparison of the conventional Apgar with the specified Apgar score and AAP-suggestion in an international prospective study. Inclusion criteria: gestational age below 33 weeks, born within participating centres. Following data were obtained: perinatal characteristics; the infant's condition during first 10 minutes; discharge data on mortality and morbidity. Results: Of the 2169 infants that were screened, 1930 were included with the following birth characteristics: GA 28±2.5, birthweight 1164±400g, umbilical artery pH 7.3±0.1. The specified Apgar score was significantly higher than the conventional score. Mortality of included infants was 11%. Comparison of infants who died or survived showed no differences in conventional Apgar score [median (range) 7(5-8) vs. 8(7-9)], however, significant differences in the specified score [6(4-7) vs. 9(8-10)]. 6% of infants did not require any support (according to AAP-form) during the first 10 minutes, infants who did not survive the neonatal period required significantly more support during the first 10 minutes. Discussion: It is the first presentation of the TEST-APGAR study-results providing data to improve the usage of Apgar-Score in infants requiring support in the delivery room.

Comparison of early pregnancy and neonatal outcomes after frozen and fresh embryo transfer in ART cycles

frozen embryo transfer (FET) has no clear negative impact on neonatal outcome compared with fresh embryo transfer (ET) and appears to result in similar or even better neonatal outcome. The objective of this study was to compare early pregnancy outcome and neonatal health of children born after FET and fresh ET. in this study early pregnancy and neonatal outcomes after FET (n = 200) and fresh ET (n = 500) were compared. for early pregnancy, biochemical pregnancy was comparable between FET and fresh ET groups. Spontaneous abortion was significantly higher in FET (14.5%) than fresh ET group (9%). Neonatal outcome was comparable between both groups except for lower live birth rate in FET (55%) versus fresh ET group (66%). FET has similar neonatal outcome in terms of prematurity, low birth weight, stillbirth, neonatal death and major malformation compared with fresh ET.

Whole Body Hypothermia and Oxidative Stress in Babies With Hypoxic-Ischemic Brain Injury

According to increasing evidence, hypothermia can significantly improve outcomes in term neonates manifesting asphyxic insult and hypoxic-ischemic encephalopathy. Oxidative stress plays a key role in hypoxic-ischemic and inflammatory brain injuries. We investigated the impact of hypothermia on oxidative stress in babies with hypoxic-ischemic encephalopathy. Term infants were randomly selected for treatment with moderate whole body hypothermia or standard care on normothermia, after perinatal asphyxia. Total hydroperoxides as biochemical markers of oxidative stress, and C-reactive protein as a marker of inflammation, were assayed in blood samples drown at 6, 12, 24, 48, and 72 postnatal hours. In both hypothermic and normothermic groups, total hydroperoxides and C-reactive protein exhibited a continuous increase in the first days after birth. Nevertheless, a tendency was evident for slower and smaller elevations of total hydroperoxides and C-reactive protein in hypothermic compared with normothermic infants. A significant correlation was observed between total hydroperoxides and C-reactive protein in all patients, indicating an association between inflammation and oxidative stress during asphyxia. The slower increase and lower peaks of total hydroperoxides in the hypothermic group support the hypothesis that postasphyxic oxidative stress may be reduced by hypothermia.

Impact of instrumental delivery in theatre on short-term neonatal outcomes: is it time for new standards?

BackgroundDecision to delivery intervals (DDI) are widely used in obstetric practice to audit emergency Caesarean sections. However, there is limited data available regarding DDI for instrumental deliveries, and there are...

Large prospective, pregnancy and infant follow-up trial assures the health of 1000 fetuses conceived after treatment with the GnRH antagonist ganirelix during controlled ovarian stimulation

A concern for new compounds in fertility treatment is the possible risk of perinatal complications or birth defects. To demonstrate long-term safety of ganirelix (GnRH antagonist) treatment in controlled ovarian stimulation (COS), follow-up data on pregnancy and neonatal outcome were analysed for 1000 fetuses (>or=16 gestational weeks). Obstetrical and neonatal data on 839 pregnancies, resulting in 969 live born infants after ganirelix treatment were compared with a historical cohort of 753 pregnancies after long GnRH agonist (buserelin) treatment, resulting in 963 live born infants. All treatment cycles were performed in a single fertility centre. The infants were examined at the Universitair Ziekenhuis Brussel using an identical follow-up protocol. Incidence of major malformations (i.e. causing functional impairment or requiring surgical correction) was the primary end-point and was analysed by logistic regression including treatment, age of mother, IVF method and pregnancy type (singleton/multiple) as independent variables. There were no relevant differences in maternal characteristics, fertilization method and pregnancy and delivery complications between the ganirelix and historical GnRH agonist groups. There were relatively more multiple pregnancies in the historical GnRH agonist group (31.9%) than the ganirelix group (18.7%; P < 0.0001). The groups were comparable with respect to pregnancy loss after 16 weeks gestation. The incidence of major congenital malformations in fetuses with gestational age >or=26 weeks was 5.0% in the ganirelix cohort versus 5.4% in the historical GnRH agonist group (odds ratio 0.94, 95% confidence interval, 0.62-1.42). In terms of neonatal outcome and risk of major malformations, treatment with the GnRH antagonist ganirelix during COS is as safe as traditional GnRH agonists.

311: Elective inductions at term and adverse neonatal outcomes

311: Elective inductions at term and adverse neonatal outcomes

Magnesium in acute and chronic brain injury: an update

While brain free magnesium levels have been shown to decline in a number of acute and chronic brain pathologies, the mechanisms of such decline and the potential for magnesium administration as a therapeutic intervention are still unclear. In acute brain injury, magnesium therapy has failed in recent clinical trials of trauma, presumably because of an intact blood brain barrier at the time of administration reducing central penetration. Under such conditions, magnesium's peripheral effects on cardiovascular parameters may dominate over the central, and potentially neuroprotective, effects of the compound. In contrast, magnesium has been demonstrated to be beneficial in lacunar strokes, albeit that recent animal studies indicate that this effect is without any significant reduction of lesion size. Postnatal magnesium has also been shown to improve neurological outcome in term neonates with perinatal asphyxia, although this may be limited to cases of mild to moderate brain injury; no effect is observed following severe brain injury. Prenatal magnesium has been reported to be beneficial for outcome in very preterm infants, although this may only be at low doses. Combination therapies are also showing promise in experimental studies, with combined magnesium and mild hypothermia as well as magnesium and polyethylene glycol proving effective in ischemic stroke and in spinal cord injury, respectively. With respect to chronic brain injury, recent results indicate that magnesium deficient mice are susceptible to developing Parkinson's disease, which is consistent with earlier findings that magnesium deficiency over a number of generations is associated with the development of Parkinson's disease. The latter was associated with the appearance of variants of the TRPM channels. Our recent studies have shown that Parkinson's disease is associated with reduced TRPM2 and TRPM7 channel mRNA expression. Taken together, a more complete picture is emerging of the role of magnesium in brain injury, its therapeutic potential as well the mechanisms associated with its decline.

Prescription drugs among pregnant women in Lome, Togo, West Africa

To assess the trends in prescription drugs and the potential repercussions to newborns among pregnant women who attended prenatal consultations and gave birth in the Department of Gynaecology of Tokoin's University Hospital, Lome (Togo). A retrospective study of the registers of prenatal visits and deliveries of the eligible population was performed. In total, 184 different drugs were prescribed to 627 pregnant women attending prenatal consultations. The profile of pharmacotherapeutic groups prescribed was: anti-anaemics (33.33%), antimalarial drugs (24.75%), vitamins +/- mineral salts, amino acids and appetite stimulants (14.96%) and antispasmodics and anti-emetics (7.22%). The median proportion of prescriptions for each pharmacotherapeutic group increased significantly from the first to third trimester (9.72, 25.17 and 64.00 respectively; P < 0.05). The median number of drugs prescribed did not vary significantly (P = 0.051) with the age groups, parity (P = 0.068) or obstetrical-gynaecological history (P = 0.401); it did, however, increase significantly with the medical-surgical history (P < 0.05). There were complications associated with deliveries that had no obvious cause related to drug prescription, including four cases of minor defects, 28 stillborns, 65 cases of low birth weight and 27 hospitalised newborns for neonatal diseases. Some interventions were needed for safeguarding the health of the mother, the foetus and the newborn. The trends in obtaining prescription drugs and the consumption of drugs by pregnant women can be assessed using multiple parameters. We limited our study to age groups, gestational age, parity and the medical history of the pregnant woman, profile of pharmacotherapeutic groups, median number of drugs prescribed and the potential risks of the drugs used. The results of our retrospective study were not alarming in terms of neonatal outcomes.

Cesarean section for suspected fetal distress, continuous fetal heart monitoring and decision to delivery time

To find out the efficacy of continuous fetal heart monitoring by analyzing the cases of cesarean section for nonreassuring fetal heart in labor, detected by cardiotocography (CTG) and correlating these cases with perinatal outcome. To evaluate whether a 30 minute decision to delivery (D-D) interval for emergency cesarean section influences perinatal outcome. This was a prospective observational study of 217 patients who underwent cesarean section at > or = 36 weeks for non-reassuring fetal heart in labor detected by CTG. The maternal demographic profile, specific types of abnormal fetal heart rate tracing and the decision to delivery time interval were noted. The adverse immediate neonatal outcomes in terms of Apgar score <7 at 5 minutes, umbilical cord thornH <7.10, neonates requiring immediate ventilation and NICU admissions were recorded. The correlation between non-reassuring fetal heart, decision to delivery interval and neonatal outcome were analyzed. Out of 3148 patients delivered at > or = 36 weeks, 217 (6.8%) patients underwent cesarean section during labor primarily for non-reassuring fetal heart. The most common fetal heart abnormality was persistent bradycardia in 106 (48.8%) cases followed by late deceleration in 38 (17.5%) cases and decreased beat to beat variability in 17 (7.8%) cases. In 33 (15.2%) babies the 5 minutes Apgar score was <7 out of which 13 (5.9%) babies had cord thornH <7.10. Thirty three (15.2%) babies required NICU admission for suspected birth asphyxia. Rest 184 (84.7%) neonates were born healthy and cared for by mother. Regarding decision to delivery interval of < or =30 minutes versus >30 minutes, there was no significant difference in the incidence of Apgar score <7 at 5 minutes, cord pH <7.10 and new born babies requiring immediate ventilation. But the need for admission to NICU in the group of D-D interval < or = 30 minutes was significantly higher compared to the other group where D-D interval was >30 minutes. Non-reassuring fetal heart rate detected by CTG did not correlate well with adverse neonatal outcome. There was no significant difference in immediate adverse neonatal outcome whether the D-D time interval was < or = 30 minutes or >30 minutes; contrary to this, NICU admission for suspected birth asphyxia in </= 30 minutes group was significantly higher.

No short-term benefits of antenatal corticosteroid treatment in severely preterm growth restricted fetuses: A case–control study

Background Antenatal corticosteroid administration to premature, growth restricted fetuses may not be beneficial and even have adverse effects on neonatal outcome. Aims To determine if preterm growth restricted fetuses benefit from antenatal corticosteroids. Study design Retrospective cohort study. Methods All singleton pregnancies with growth restricted fetuses delivered at our department before 34 weeks' gestation or weighing less than 1500 g, between January 2001 and December 2005, were retrospectively reviewed. Neonatal outcome was compared between growth restricted fetuses (defined as abnormal flow patterns in umbilical and middle cerebral arteries) that received antenatal CST (CST group) and those who did not receive antenatal CST (no CST group). The administration of CST appeared to be quasi randomized. Results A total of 88 pregnancies fulfilled the inclusion criteria (CST group, n = 54; no CST group, n = 34). The incidence of neonatal respiratory distress syndrome in the CST and no CST group was 42% (22/54) and 50% (17/34), respectively ( p = 0.44). Neonatal mortality in the CST and no CST group was 9% (5/54) and 12% (4/34), respectively ( p = 0.73). The prevalence of adverse neonatal outcome (neonatal mortality, major neonatal morbidity or severe cerebral lesions) in the CST and no CST group was 28% (15/54) versus 24% (8/34), ( p = 0.62). Conclusions Administration of CST to growth restricted preterm fetuses does not appear to be beneficial with respect to short term neonatal outcome.

Patterns of brain injury and outcome in term neonates presenting with postnatal collapse

Objective:To document perinatal events, brain imaging, neurophysiology and clinical outcome in term infants with early postnatal collapse (PNC).Design:Tertiary referral centre, retrospective case review (1993–2006).Patients:Infants born at ⩾36 weeks’ gestation with...

Is There a Way to Predict Outcome in (Near) Term Neonates with Hypoxic-Ischemic Encephalopathy Based on MR Imaging?

It has previously been demonstrated that comparison of signal intensity (SI) between selected brain structures on T1-weighted images enables distinction between the absence or presence of hypoxic-ischemic (HI) brain injury in young infants. The aim of the present study was to assess whether this method of brain structure T1-weighted SI comparison also enables prediction of outcome. Survivors of a group of 57 children with neonatal HI encephalopathy (HIE) grade 2 or 3 according to Sarnat and Sarnat and controls who underwent neonatal MR imaging were retrospectively assigned to 1 of 3 outcome groups at 5 years of age, depending on developmental outcome: 1) normal, 2) mildly abnormal, and 3) definitely abnormal. Gestational age was not significantly different between the HIE group (range, 35 + 5-42 + 5 weeks; mean, 39 + 4 weeks) and control group (range, 35 + 0-42 + 1 weeks; mean, 39 + 2 weeks). We calculated the predictive values of the neonatal clinical HIE classification according to Sarnat and Sarnat for outcome (neonatal death and developmental outcome in survivors). We assessed which brain structure T1-weighted SI comparison scored best for outcome prediction. Predictive values of that comparison for outcome were calculated for the entire group and for the HIE grade 2 group only, a patient group with highly variable outcome. Of the 57 children, 6 died. Outcome group 1 consisted of 31; group 2, of 14; and group 3, of 6 children. The positive predictive value of the neonatal clinical classification for adverse outcome (outcome group 3 and death) was 52%; and negative predictive value, 100%. These were respectively 45% and 0% in children with HIE grade 2. Of all brain structure T1-weighted SI comparisons, that of the posterior limb of the internal capsule versus the posterolateral putamen scored best for outcome prediction. The positive predictive value for adverse outcome was 69%; and negative predictive value, 98%. In children with HIE grade 2, the positive predictive value and negative predictive value for adverse outcome were 67% and 88%. Brain structure T1-weighted SI comparisons are helpful to predict outcome in (near) term neonates with HIE. This finding adds to the current knowledge and clinical practice. If the SI in the posterolateral putamen is less than the SI in the posterior limb of the internal capsule, favorable outcome is very likely, whereas if the SI in the posterolateral putamen is equal to or greater than the SI in the posterior limb of the internal capsule, adverse outcome is very likely. In neonates with HIE grade 2 according to Sarnat and Sarnat, prediction of outcome is substantially improved by using these brain structure T1-weighted SI comparisons.

MRC ORACLE Children Study. Long term outcomes following prescription of antibiotics to pregnant women with either spontaneous preterm labour or preterm rupture of the membranes

BackgroundThe Medical Research Council (MRC) ORACLE trial evaluated the use of co-amoxiclav 375 mg and/or erythromycin 250 mg in women presenting with preterm rupture of membranes (PROM) ORACLE I or in spontaneous preterm labour (SPL) ORACLE II using a factorial design. The results showed that for women with a singleton baby with PROM the prescription of erythromycin is associated with improvements in short term neonatal outcomes, although co-amoxiclav is associated with prolongation of pregnancy, a significantly higher rate of neonatal necrotising enterocolitis was found in these babies. Prescription of erythromycin is now established practice for women with PROM. For women with SPL antibiotics demonstrated no improvements in short term neonatal outcomes and are not recommended treatment. There is evidence that both these conditions are associated with subclinical infection so perinatal antibiotic administration may reduce the risk of later disabilities, including cerebral palsy, although the risk may be increased through exposure to inflammatory cytokines, so assessment of longer term functional and educational outcomes is appropriate.MethodsThe MRC ORACLE Children's Study will follow up UK children at age 7 years born to 4809 women with PROM and the 4266 women with SPL enrolled in the earlier ORACLE trials. We will use a parental questionnaire including validated tools to assess disability and behaviour. We will collect the frequency of specific medical conditions: cerebral palsy, epilepsy, respiratory illness including asthma, diabetes, admission to hospital in last year and other diseases, as reported by parents.National standard test results will be collected to assess educational attainment at Key Stage 1 for children in England.DiscussionThis study is designed to investigate whether or not peripartum antibiotics improve health and disability for children at 7 years of age.Trial registrationThe ORACLE Trial and Children Study is registered in the Current Controlled Trials registry. ISCRTN 52995660

Medikamentöse und nichtmedikamentöse Schmerztherapie in der Neonatologie: Zusammenstellung der aktuellen Datenlage

There is increasing knowledge about the negative consequences of early pain experiences on the acute and long-term outcome of preterm and term neonates. Despite of it, pain is common in neonatal intensive care. Pharmacologic and nonpharmacologic methods of pain therapy with variable analgesic efficacy exist. The aim of this article is to give a compendium of the actual strategies of pain therapies for invasive procedures, endotracheal suctioning, eye-examination and for mechanical ventilation of preterm and term neonates. An evaluation of benefits and drawbacks of the single pain alleviating measures will be done.

Cerebral function monitoring: a method of predicting outcome in term neonates after severe perinatal asphyxia.

The cerebral function monitor (CFM), a simplified one-channel EEG monitor, was evaluated in predicting outcome after severe perinatal asphyxia in 38 term infants. Survivors were followed until 1.5-2.5 years of age. All those 17 infants who survived without major neurological handicap showed continuous activity on the CFM trace during the first and/or second day of life. Twenty of the 21 infants who either died or developed severe neurological damage had burst suppression or paroxysmal activity on the first or second day of life. Thus cerebral function monitoring can be a valuable tool in predicting prognosis for infants with severe perinatal asphyxia.

65: In utero oxygen reactivity in fetuses with congenital diaphragmatic hernia and correlations with postnatal respiratory function

HERNIA AND CORRELATIONS WITH POSTNATAL RESPIRATORY FUNCTION ELISA DONE, LEONARDO GUCCIARDO, TIM VAN MIEGHEM, JACQUES JANI, ANNE DEBEER, GUNNAR NAULAERS, JAN DEPREST, University Hospitals Leuven, OB/GYN, Leuven, Belgium, University Hospitals Leuven, Neonatology, Leuven, Belgium OBJECTIVE: To correlate fetal pulmonary artery reactivity to maternal O2 administration with neonatal respiratory parameters in fetuses with congenital diaphragmatic hernia (CDH). STUDY DESIGN: Lung vascular reactivity was tested in 22 fetuses with CDH using measurement of pulsatility index (PI) in the 1st branch of the contralateral pulmonary artery before and after maternal 60%O2 by mask. A decrease of 20% in PI after O2 exposure was considered reactive. Measuraments were performed before and after 30 weeks (TEST1 between 26-30wks, TEST2, between 30 and term) with at least 3 wks interval (mean 5.3).Fetuses were either expectantly managed (n 8) or severe cases underwent fetal endoscopic tracheal occlusion (FETO: 26.4 -31.1; removal: 33.5-35.4 wks) (n 14). Oxygenation Index (OI) and alveolar-arterial oxygen gradient (D(A-a)O2 are prognostic measures of respiratory performance in newborns with pulmonary dysfunction. OI is based on mean airway pressure (MAP), inspired O2 fraction (FiO2) and pO2 values. D(A-a)O2 is function of pO2 and pCO2 levels. We measured hourly in the first 8 hours after birth. We compared means of OI and D(A-a)O2 at each time point between groups and in terms of previous reactivity to oxygen. RESULTS: Median GA at TEST1 and TEST2 was 27.2 wks (26-29.6) resp 34.3 wks (30.1-38.2) and 37 wks (32-39.3) at delivery. 9/22 fetuses had reactive oxygen tests in pregnancy (TEST1&2 positive, n 3) or only late in gestation (TEST2 positive, n 6). They had significantly lower OI and D(A-a)O2 at the 1st, 2nd and 3rd hour of life than non-reactive fetuses (p 0.05). D(A-a) was significantly related to the decrease in pulmonary resistance during TEST2 (p 0.05). 77 % of these survived till discharge. Conversely, fetuses without reactive test at any stage (n 13) had significantly higher OI and D(A-a)O2 values. Only 23 % (n 3) of them survived. CONCLUSION: In utero pulmonary vascular reactivity to O2 is related to postnatal respiratory parameters in the first hours of life. It may be used to predict ventilatory performance and short term neonatal outcome in CDH fetuses.

A systematic review of cooling for neuroprotection in neonates with hypoxic ischemic encephalopathy – are we there yet?

BackgroundThe objective of this study was to systematically review randomized trials assessing therapeutic hypothermia as a treatment for term neonates with hypoxic ischemic encephalopathy.MethodsThe Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL databases, reference lists of identified studies, and proceedings of the Pediatric Academic Societies were searched in July 2006. Randomized trials assessing the effect of therapeutic hypothermia by either selective head cooling or whole body cooling in term neonates were eligible for inclusion in the meta-analysis. The primary outcome was death or neurodevelopmental disability at ≥ 18 months.ResultsFive trials involving 552 neonates were included in the analysis. Cooling techniques and the definition and severity of neurodevelopmental disability differed between studies. Overall, there is evidence of a significant effect of therapeutic hypothermia on the primary composite outcome of death or disability (RR: 0.78, 95% CI: 0.66, 0.92, NNT: 8, 95% CI: 5, 20) as well as on the single outcomes of mortality (RR: 0.75, 95% CI: 0.59, 0.96) and neurodevelopmental disability at 18 to 22 months (RR: 0.72, 95% CI: 0.53, 0.98). Adverse effects include benign sinus bradycardia (RR: 7.42, 95% CI: 2.52, 21.87) and thrombocytopenia (RR: 1.47, 95% CI: 1.07, 2.03, NNH: 8) without deleterious consequences.ConclusionIn general, therapeutic hypothermia seems to have a beneficial effect on the outcome of term neonates with moderate to severe hypoxic ischemic encephalopathy. Despite the methodological differences between trials, wide confidence intervals, and the lack of follow-up data beyond the second year of life, the consistency of the results is encouraging. Further research is necessary to minimize the uncertainty regarding efficacy and safety of any specific technique of cooling for any specific population.

Concurrent versus sequential methods for labor induction at term

Objective To determine the efficacy and safety of the concurrent administration of oxytocin and prostaglandin E2 (PGE2) for induction of labor at term, prompt delivery, and good maternal and neonatal outcomes. Methods In this comparative cohort study of 70 women conducted in Pakistan, 35 were given oxytocin and PGE2 concurrently and 35 were given the drugs sequentially for labor induction. Two-sample t tests and × 2 tests were used for the evaluation of continuous and categorical data, respectively. Results The mean induction to delivery time was shorter by 2.4 h in the concurrent treatment group ( P < 0.001), and the proportion of vaginal deliveries was higher in that group. Conclusion The concurrent method of induction of labor resulted in shorter induction to delivery time and a higher proportion of vaginal deliveries.

Predicting outcome in term neonates with hypoxic-ischaemic encephalopathy using simplified MR criteria

Predicting outcome in term neonates with hypoxic-ischaemic encephalopathy using simplified MR criteria

Developmental pharmacokinetics of opioids in neonates

Recognition and treatment of pain are now important indicators of the quality of care being delivered to neonates. However, population-specific characteristics have to be considered, necessitating an integrated, population-specific approach. Such an approach starts with a systematic evaluation ofpain, using a validated pain-assessment instrument, and should be followed by effective interventions, mainly based on appropriate, i.e., safe and effective, administration of analgesics. We will illustrate the impact of age on the pharmacokinetics and metabolism of opioids using recently collected and reported observations of tramadol disposition in early neonatal life. Although distribution volume and clearance display age-dependent maturation, it is important to recognize that important, unexplained interindividual variability in drug metabolism is still observed. Research questions in the field of developmental pharmacokinetics of opioids should focus on covariables of relevance in the interindividual variability of both pharmacokinetics and pharmacodynamics of opioids in neonates and on long-term outcomes in preterm and term neonates to whom opioids were administered, with regard to behavioral consequences and effects on pain thresholds.