Ecological momentary assessment of maternal cortisol profiles over a multiple-day period predicts the length of human gestation.

OBJECTIVE: Biobehavioral models of prenatal stress highlight the importance of the stress-related hormone cortisol. However, the association between maternal cortisol levels and the length of human gestation requires further investigation because most previous studies have relied on one-time cortisol measures assessed at varying gestational ages. This study assessed whether ecological momentary assessment (EMA) of cortisol sampling improves the ability to predict the length of human gestation. In addition, associations between EMA-based measures of psychological state (negative affect) with cortisol levels during pregnancy were assessed. METHODS: For a 4-day period, 25 healthy pregnant women (mean gestational age at assessment = 23.4 [standard deviation = 9.1] weeks) collected seven salivary samples per day for the assessment of cortisol and provided a rating of negative affect every waking hour using an electronic diary. RESULTS: Higher salivary cortisol concentrations at awakening and throughout the day (p = .001), as well as a flatter cortisol response to awakening (p = .005), were associated with shorter length of gestation. Women who delivered an infant at 36 weeks of gestations had 13% higher salivary cortisol levels at awakening than women who delivered an infant at 41 weeks of gestation. The EMA-based measure of negative affect was associated with higher cortisol throughout the day (p = .006) but not to gestational length (p = .641). The one-time measure of cortisol was not associated with length of gestation, and traditional retrospective recall measures of negative affect were not associated with cortisol. CONCLUSIONS: Our findings support the ecological validity of repeated ambulatory assessments of cortisol in pregnancy and their ability to improve the prediction of adverse birth outcomes.

Prenatal beta-endorphin as an early predictor of postpartum depressive symptoms in euthymic women.

BACKGROUND: After delivery, many women experience symptoms of postpartum depression (PPD), and early identification of women at risk is therefore important. The opioid peptide beta-endorphin has been implicated in non-puerperal depression but its role in the development of PPD is unknown. METHODS: Three hundred and seven women with a singleton, full-term (>37.0 weeks' GA) pregnancy were recruited early in pregnancy and followed up into the postpartum period. Blood samples were obtained at 15, 19, 25, 31 and 37 weeks' gestational age (GA) and at 9 weeks postpartum for assessment of beta-endorphin. Depressive symptoms were assessed with the Center for Epidemiological Studies-Depression scale at the last four pregnancy visits and with the Edinburgh Postnatal Depression Scale postpartum. RESULTS: Among women who were euthymic at 25 weeks' GA, those who proceeded to develop PPD symptoms had higher levels of beta-endorphin throughout pregnancy compared to women without PPD symptoms (all t>2.11, p<.05). At each assessment, women above the cut-off score for beta-endorphin were at more than three-fold risk for PPD symptoms (odds ratios 3.19-4.68) compared to women below the cut-off score. LIMITATIONS: Self-report of depressive symptoms, no mental health history. CONCLUSIONS: Beta-endorphin may be a useful early predictor of PPD symptoms in women who do not report depressive symptoms in mid-pregnancy. If replicated, these findings have clinical implications for the identification and treatment of this at-risk group and further suggest that some of the pathways leading to this complex disorder may be specific to subgroups of women.

Attenuation of maternal psychophysiological stress responses and the maternal cortisol awakening response over the course of human pregnancy.

The effects of maternal stress during pregnancy may depend, in part, on the timing in gestation of the occurrence of stress. The aim of the present study was to examine the effect of stage of gestation on maternal psychophysiological responses to stress using a standardized laboratory paradigm and on the cortisol response to awakening (CAR). A longitudinal design was employed to quantify maternal psychophysiological stress reactivity [changes in heart rate (HR), blood pressure, salivary cortisol, and psychological distress in response to the trier social stress test (TSST)] and the CAR at approximately 17 and 31 weeks gestation in a sample of 148 women. To account for the possible effects of habituation when being exposed to the same stress protocol twice, a non-pregnant comparison group (CG, N = 36) also underwent these assessments at two time points, with a comparable time interval between the assessments. In both groups, the TSST elicited significant changes in maternal HR, mean arterial pressure, and psychological distress levels but not a significant increase in cortisol levels. Among the pregnant women (pregnant group(PG)), the stressor-induced increases in HR, blood pressure, and psychological distress were significantly lower at the second (31 weeks gestation) compared to the first (17 weeks gestation) assessment of pregnancy (all p < 0.01). The maternal CAR was also significantly attenuated in later compared to earlier gestation (p = 0.003). In the CG, there were no significant differences in psychophysiological stress responses and in the CAR across the two assessments. Among pregnant women there is a progressive attenuation of psychophysiological stress responses with advancing gestation. This attenuation is unlikely to be attributable to habituation. Individual differences in the degree of attenuation of stress responses over gestation may represent a novel marker of stress susceptibility in human pregnancy.

The maternal cortisol awakening response in human pregnancy is associated with the length of gestation.

OBJECTIVE: The purpose of this study was to examine the relationship between intraindividual changes in cortisol responsiveness over pregnancy and the length of human gestation. STUDY DESIGN: Pregnancy-related changes in the cortisol awakening response (CAR), which is a measure of hypothalamic-pituitary-adrenal axis responsiveness, were assessed prospectively in 101 pregnant women at 16.8 +/- 1.4 weeks' and 31.4 +/- 1.3 weeks' (+/-SD) gestation. Cortisol was measured in saliva that was collected immediately and +30, +45 and +60 minutes after awakening. RESULTS: The CAR was significant in pregnancy and exhibited progressive attenuation over the course of gestation. A larger CAR in late pregnancy and reduced attenuation of the CAR from early to late gestation were associated significantly with shorter gestational length. CONCLUSION: The findings are the first to suggest that the hormonal (cortisol) response to a naturally occurring challenge (awakening) and the degree of attenuation of this response over the course of gestation may represent a novel biomarker of increased vulnerability for earlier birth.

Risk of postpartum depressive symptoms with elevated corticotropin-releasing hormone in human pregnancy.

CONTEXT: Postpartum depression (PPD) is common and has serious implications for the mother and her newborn infant. A possible link between placental corticotropin-releasing hormone (pCRH) and PPD incidence has been hypothesized, but empirical evidence is lacking. OBJECTIVE: To determine whether accelerated increases in pCRH throughout pregnancy are associated with PPD symptoms. DESIGN: Pregnant women were recruited into this longitudinal cohort study. Blood samples were obtained at 15, 19, 25, 31, and 37 weeks' gestational age (GA) for assessment of pCRH, cortisol, and adrenocorticotropic hormone (ACTH). Depressive symptoms were assessed with a standardized questionnaire at the last 4 pregnancy visits and post partum. SETTING: Subjects were recruited from 2 southern California medical centers, and visits were conducted in research laboratories. PARTICIPANTS: One hundred adult women with a singleton pregnancy. Main Outcome Measure Symptoms of PPD were assessed at a mean (SD) of 8.7 (2.94) weeks after delivery with the Edinburgh Postnatal Depression Scale. RESULTS: Sixteen women developed PPD symptoms. At 25 weeks' GA, pCRH was a strong predictor of PPD symptoms (R(2) = 0.21; beta = 0.46 [P < .001]), an effect that remained significant after controlling for prenatal depressive symptoms. No significant associations were found for cortisol and ACTH. Receiver operating characteristic curve analyses revealed that pCRH at 25 weeks' GA is a possible diagnostic tool (area under the curve, 0.78 [P = .001]). Sensitivity (0.75) and specificity (0.74) at the ideal cutoff point (pCRH, 56.86 pg/mL) were moderate. Growth curve analyses indicated that the trajectories of pCRH in women with PPD symptoms are significantly accelerated from 23 to 26 weeks' GA. CONCLUSIONS: At a critical period in midpregnancy, pCRH is a sensitive and specific early diagnostic test for PPD symptoms. If replicated, these results have implications for the identification and treatment of pregnant women at risk for PPD.

The role of proopiomelanocortin (POMC) in sequentially dependent self-injurious behavior.

Self-injuring behavior (SIB) is a life-threatening behavior exhibited by many species, including humans, and has no known cause and no agreed upon treatment. The role of the stress axis in the maintenance of this mysterious behavior was examined in subjects with life-long SIB. Over a 6-year period, 40 hr of direct observations of behavior and the environment were recorded on palmtop computers while 36 residential subjects (28 target and 8 control subjects) conducted their daily activities. Blood samples were collected in morning and evening for all subjects and within minutes after a self-injuring act in 28 target subjects who exhibited SIB to determine levels of ACTH and B-endorphin (BE). Self-injuring events in the patient group were significantly sequentially dependent (i.e., the only predictor of a self-injuring act was an antecedent self-injuring act). Higher morning levels of BE relative to ACTH predicted [r(df=27) = .57, p < .001] the sequentially dependent pattern of SIB. This effect was validated in a subgroup retested several months later [r(df=22) = .60, p < .001]. A subgroup of seven subjects exhibiting sequentially dependent patterns were administered an opiate blocker (naltrexone) in a double-blind, crossover design with an additional 14 hr/week of observation for 7 weeks. Naltrexone challenge interrupted the sequential pattern (improved behavior) in subjects with elevated BE immediately following SIB (r = .85, p < .01). The pattern of results supported the conclusion that the stress axis played a significant role in the maintenance of complex episodes of self-injury.

Timing of fetal exposure to stress hormones: effects on newborn physical and neuromuscular maturation.

The purpose of the study was to determine the specific periods during pregnancy in which human fetal exposure to stress hormones affects newborn physical and neuromuscular maturation. Blood was collected from 158 women at 15, 19, 25, and 31 weeks' gestation. Levels of placental corticotropin-releasing hormone (CRH) and maternal cortisol were determined from plasma. Newborns were evaluated with the New Ballard Maturation Score. Results indicated that increases in maternal cortisol at 15, 19, and 25 weeks and increases in placental CRH at 31 weeks were significantly associated with decreases in infant maturation among males (even after controlling for length of gestation). Results also suggested that increases in maternal cortisol at 31 weeks were associated with increases in infant maturation among females, although these results were not significant after controlling for length of gestation. Findings suggest that stress hormones have effects on human fetal neurodevelopment that are independent of birth outcome.

Temporal patterns of self-injurious behavior correlate with stress hormone levels in the developmentally disabled.

While the origins and developmental course of self-injurious behavior (SIB) remain relatively unknown, recent studies suggest a biological imbalance may potentiate or provoke the contagious recurrence of SIB patterns in individuals with severe developmental disabilities (DD). Evidence from several laboratories indicates that functioning, relations, and processing of a stress-related molecule, proopiomelanocortin (POMC) may be perturbed among certain subgroups of individuals exhibiting SIB. The current investigation employed a unique time-pattern analysis program (THEME) to examine whether recurrent temporal patterns (T-patterns) of SIB were related to morning levels of two POMC-derived hormones: beta-endorphin (betaE) and adrenocorticotropic hormone (ACTH). THEME was used to quantify highly significant (non-random) T-patterns that included SIB within a dataset of in situ observational recordings spanning 8 days ( approximately 40 h) in 25 subjects with DD. Pearson's product-moment analyses revealed highly significant correlations between the percentage of T-patterns containing SIB and basal levels of both betaE and ACTH, which were not found with any other "control" T-patterns. These findings support the hypothesis that the recurrent temporal patterning of SIB represents a unique behavioral phenotype directly related to perturbed levels of POMC-derived stress hormones in certain individuals with severe DD.

Low levels of corticotropin-releasing hormone during early pregnancy are associated with precocious maturation of the human fetus.

Elevation in placental corticotropin-releasing hormone (pCRH) during the last trimester of pregnancy has been associated with an increased risk for preterm delivery. Less is known about the consequences for the human fetus exposed to high levels of pCRH early in pregnancy. pCRH levels were measured in 138 pregnant women at least once at 15, 20 and 25 weeks of gestation. At 25 weeks of gestation, fetal heart rate (FHR) responses to a startling vibroacoustic stimulus (VAS) were recorded as an index of maturity. pCRH levels at 15 weeks of gestation, but at no later point, predicted FHR responses to the VAS. Fetuses exposed to the lowest concentrations of pCRH at 15 weeks of gestation exhibited a distinguishable response to the VAS, whereas fetuses exposed to higher levels of pCRH did not respond. The findings suggest that exposure to low levels of pCRH early in gestation may be optimal and associated with a response pattern indicating greater maturity.

Beta-endorphin levels in longtailed and pigtailed macaques vary by abnormal behavior rating and sex.

Frequent or severe abnormal behavior may be associated with the release of endorphins that positively reinforce the behavior with an opiate euphoria or analgesia. One line of research exploring this association involves the superhormone, proopiomelanocortin (POMC). The products of POMC appear to be dysregulated in some human subjects who exhibit self-injurious behavior (SIB). Macaque monkeys have POMC very similar to humans, and some laboratory macaques display SIB or frequent stereotypies. We investigated associations between plasma levels of three immunoreactive POMC fragments with possible opioid action and abnormal behavior ratings in macaques. In 58 adult male and female macaques (24 Macaca fascicularis and 34 Macaca nemestrina), plasma levels of intact beta-endorphin (betaE) and the N-terminal fragment (BEN) were significantly higher in animals with higher levels of abnormal behavior. The C-terminal fragment (BEC) was significantly higher in males but unrelated to ratings of abnormal behavior. Levels of ACTH, cortisol, and (betaE-ACTH)/betaE dysregulation index were unrelated to abnormal behavior. None of the POMC products differed significantly by subjects' species, age, or weight. The finding that intact beta-endorphin is positively related to abnormal behavior in two species of macaque is consistent with some previous research on human subjects and nonprimates. The positive relation of the N-terminal fragment of betaE to abnormal behavior is a new finding.

Ethnic differences in adrenocorticotropic hormone, cortisol and corticotropin-releasing hormone during pregnancy.

Significant ethnic disparities exist in reproductive outcomes. A potential contributing factor may be the functioning of the hypothalamic-pituitary-adrenal (HPA) axis and placenta during pregnancy. In the present study, levels of cortisol, ACTH and CRH were determined longitudinally from the plasma of 310 African American, Hispanic and non-Hispanic White women at 18-20, 24-26 and 30-32 weeks' gestation. During pregnancy, African American women exhibited lower levels of cortisol than non-Hispanic women and higher levels of ACTH than Hispanic women. The trajectory of CRH increase also differed by ethnicity, with African Americans exhibiting the lowest levels both early and late in pregnancy. Higher levels of cortisol at 18-20 weeks were associated with higher levels of CRH at 30-32 weeks among the African American and Hispanic women, but not among non-Hispanic women. Ethnic differences persisted when adjusting statistically for sociodemographic and biomedical factors. The findings are consistent with the possibility that ethnic disparities in adverse birth outcomes may be due, in part, to differences in HPA axis and placental function.

Prenatal exposure to maternal depression and cortisol influences infant temperament.

BACKGROUND: Accumulating evidence indicates that prenatal maternal and fetal processes can have a lasting influence on infant and child development. Results from animal models indicate that prenatal exposure to maternal stress and stress hormones has lasting consequences for development of the offspring. Few prospective studies of human pregnancy have examined the consequences of prenatal exposure to stress and stress hormones. METHOD: In this study the effects of prenatal maternal psychosocial (anxiety, depression, and perceived stress) and endocrine (cortisol) indicators of stress on infant temperament were examined in a sample of 247 full-term infants. Maternal salivary cortisol and psychological state were evaluated at 18-20, 24-26, and 30-32 weeks of gestation and at 2 months postpartum. Infant temperament was assessed with a measure of negative reactivity (the fear subscale of the Infant Temperament Questionnaire) at 2 months of age. RESULTS: Elevated maternal cortisol at 30-32 weeks of gestation, but not earlier in pregnancy, was significantly associated with greater maternal report of infant negative reactivity. Prenatal maternal anxiety and depression additionally predicted infant temperament. The associations between maternal cortisol and maternal depression remained after controlling for postnatal maternal psychological state. CONCLUSIONS: These data suggest that prenatal exposure to maternal stress has consequences for the development of infant temperament.

Postnatal maternal cortisol levels predict temperament in healthy breastfed infants.

BACKGROUND: The implications of the biologically active elements in breast milk for the breastfed infant are largely unknown. Animal models suggest that ingestion of glucocorticoids during the neonatal period influences fear behavior and modifies brain development. AIMS: To determine the association between postnatal maternal cortisol levels and temperament in breastfed infants. STUDY DESIGN: The relation between maternal cortisol and infant temperament was examined in breastfed and formula-fed infants. Plasma cortisol was used as a surrogate measure for breast milk cortisol levels (plasma and milk levels are correlated in the 0.6 to 0.7 range; [Patacchioli FR, Cigliana G, Cilumbriello A, Perrone G, Capri O, Alemà GS, et al. Maternal plasma and milk free cortisol during the first 3 days of breast-feeding following spontaneous delivery or elective cesarean section. Gynecologic and Obstetric Investigations 1992;34:159-163.]. If exposure to elevated cortisol levels during infancy influences temperament, then a relation between the two should be found among the breastfed infants, but not among the formula-fed infants. SUBJECTS: Two hundred fifty-three two-month-old infants and their mothers. OUTCOME MEASURES: Fearful temperament assessed with the Infant Behavior Questionnaire [Garstein MR, Rothbart MK. Studying infant temperament via the revised infant behavior questionnaire. Infant Behavior and Development 2003;26:64-86]. RESULTS: Among the breastfed infants, higher maternal cortisol levels were associated with reports of increased infant fear behavior (partial r=0.2; p<0.01). This relation did not exist among the formula-fed infants. Negative maternal affect at the time of assessment did not account for the positive association in the breastfed group. CONCLUSIONS: The findings are consistent with our proposal that exposure to cortisol in breast milk influences infant temperament. Biologically active components in breast milk may represent one avenue through which the mother shapes the development of the human infant during the postnatal period.

Moods in everyday situations: effects of combinations of different arousal-related factors.

OBJECTIVE: This study examined women's mood responsiveness associated with patterns of stress hormone levels in everyday situations. METHODS: Self-reports of negative, positive, and energy dimensions of mood were obtained from 203 nurses throughout the day on a workday and on an off-work day during the luteal and follicular phases of the menstrual cycle. Individual differences in daytime norepinephrine and cortisol were assessed. RESULTS: Patterns of norepinephrine and cortisol levels were associated with ratings of the following moods: tired, sad, and happy. Phase of the menstrual cycle and the day factor (workday, off-work day) modified the association of mood ratings and stress hormone patterns. CONCLUSION: The experience of negative mood is associated with both hypoarousal and hyperarousal conditions. A homeostatic arousal-related concept of mood regulation is discussed.

Elevated maternal cortisol early in pregnancy predicts third trimester levels of placental corticotropin releasing hormone (CRH): priming the placental clock.

The purposes of this study were to determine the intervals when placental corticotrophic-releasing hormone (CRH) was most responsive to maternal cortisol. A sample of 203 women each were evaluated at 15, 19, 25 and 31 weeks gestation and followed to term. Placental CRH and maternal adrenocorticotropin hormone (ACTH), B-endorphin and cortisol were determined from plasma. CRH levels increased faster and were higher in women who delivered preterm compared with women who delivered at term (F3,603 = 5.73, p < .001). Simple effects indicated that CRH levels only at 31 weeks predicted preterm birth (F1,201 = 5.53, p = .02). Levels of cortisol were higher in women who delivered preterm at 15 weeks gestation (F1,201 = 4.45, p = .03) with a similar trend at 19 weeks gestation. Hierarchical regression suggested that the influence on birth outcome of maternal cortisol early in pregnancy was mediated by its influence on placental CRH at 31 weeks. Elevated cortisol at 15 weeks predicted the surge in placental CRH at 31 weeks (R = .49, d.f. = 1,199, Fchange = 61.78, p < .0001). Every unit of change in cortisol (microg/dl) at 15 weeks was associated with a 34 unit change of CRH (pg/ml) at 31 weeks. These findings suggested that early detection of stress signals by the placenta stimulated the subsequent release of CRH and resulted in increased risk for preterm delivery.

Corticotropin-releasing hormone during pregnancy is associated with infant temperament.

During pregnancy corticotropin-releasing hormone (CRH) is released into maternal and fetal circulation from the placenta. Elevated concentrations of placental CRH are associated with spontaneous preterm birth, but the consequences for infant development, independent of birth outcome, are unknown. In this study, the effects of placental CRH on infant temperament were examined in a sample of 248 full-term infants. Maternal blood samples were collected at 19, 25 and 31 weeks of gestation for CRH analysis. Infant temperament was assessed with measures of fear and distress at 2 months of age. Infants of mothers with low CRH at 25 weeks of gestation scored lower in fear and distress at 2 months. CRH at 19 and 31 weeks' gestation was not significantly associated with measures of infant temperament, suggesting the possibility that there is a sensitive period for its effects. These data suggest that prenatal exposure to CRH may exert influences that persist into the postnatal period.

Moods in everyday situations: effects of menstrual cycle, work, and stress hormones.

OBJECTIVE: This study examined women's mood responsiveness on work and off days during different phases of the menstrual cycle. METHODS: Self-reports of negative, positive, and energy dimensions of mood were obtained throughout the day on two work and two off days during the luteal and follicular phases of the menstrual cycle in 203 women nurses. Individual differences in daytime and nighttime epinephrine, norepinephrine, and cortisol were assessed. RESULTS: High daytime norepinephrine, epinephrine, and cortisol levels were associated with higher ratings of stress and tired, and with lower ratings of happy. The phase of the menstrual cycle and the day factor (workday, off day) were also associated with mood differences, and the direction of the effects depended on hormone levels and hormone sampling period. CONCLUSION: The experience of moods is affected by the arousal-related interaction of hormone levels with the phase of the menstrual cycle and occupational stress.

Placental corticotropin-releasing hormone (CRH), spontaneous preterm birth, and fetal growth restriction: a prospective investigation.

OBJECTIVES: Recent advances in the physiology of human pregnancy have implicated placental corticotropin-releasing hormone (CRH) as one of the primary endocrine mediators of parturition and possibly also of fetal development. The aim of this study was (1) to prospectively assess the relationship of maternal plasma concentrations of CRH in the early third trimester of gestation with two prematurity-related outcomes-spontaneous preterm birth (PTB), and small-for-gestational age birth (SGA), and (2) to determine whether the effects of CRH on each of these outcomes are independent from those of other established obstetric risk factors. STUDY DESIGN: In a sample of 232 women with a singleton, intrauterine pregnancy, maternal plasma was collected at 33 weeks' gestation and CRH concentrations were determined by radioimmunoassay. Each pregnancy was dated on the basis of last menstrual period and early ultrasonography. Parity, obstetric risk conditions for prematurity, mode of delivery, and birth outcomes were abstracted from the medical record. RESULTS: After adjusting for the effects of established obstetric risk factors, elevated CRH levels at 33 weeks' gestation were significantly associated with a 3.3-fold increase in the adjusted relative risk (RR) for spontaneous preterm birth and with a 3.6-fold increase in the adjusted relative risk for fetal growth restriction. Women who delivered postterm had significantly lower CRH levels in the early third trimester than those who delivered at term. When outcomes were stratified by gestational length and birth weight, the lowest CRH levels at 33 weeks' gestation were associated with the term non-SGA births, intermediate and approximately equal CRH levels were associated with the preterm non-SGA and term SGA births, and the highest CRH levels were associated with the preterm SGA births. CONCLUSION: For deliveries occurring after 33 weeks' gestation (the time of CRH sampling in this study), our findings support the notion that in humans placental CRH may play an impending, direct role in not only the physiology of parturition but also in processes related to fetal growth and maturation. Our results also support the notion that the timing of onset of parturition may be determined or influenced by events occurring earlier in gestation rather than those close to the time of actual onset of labor (ie, the notion of a "placental clock").

Selective serotonin reuptake inhibitor-related extrapyramidal symptoms in autistic children: a case series.

Abnormal movements occur rarely with selective serotonin reuptake inhibitors (SSRIs). This report describes four consecutive autistic children who developed extrapyramidal side effects (EPS) following SSRI exposure. Videotapes, physician notes, and parental interviews were used retrospectively to rate symptoms on the Extrapyramidal Symptom Rating Scale. Findings suggest that EPS is a potential complication of SSRI treatment in autistic children.

beta-Endorphin and ACTH are dissociated after self-injury in adults with developmental disabilities.

Relations between self-injuring behavior (SIB), the hypothalamic-pituitary-adrenal (HPA) stress axis, and response to an opiate antagonist were examined. Subjects were observed in their residential settings, while behavior was recorded. Blood was collected in the morning, evening, and immediately after SIB. Plasma beta-E was uncoupled from ACTH after SIB but not during the morning baseline. A significant number of the subjects (a) reduced their SIB at least 25% at all doses of naltrexone (NTX) and (b) reduced their SIB over 50% for at least one dose of NTX. The lowest dosage of NTX significantly reduced SIB in subjects with baseline levels of beta-E higher than after SIB. Results support previous reports that the HPA axis is disturbed among subjects exhibiting SIB.