Susan Berman

Antimicrobial peptides in amniotic fluid: defensins, calprotectin and bacterial/permeability-increasing protein in patients with microbial invasion of the amniotic cavity, intra-amniotic inflammation, preterm labor and premature rupture of membranes

Objective: Neutrophil defensins (HNP 1-3), bactericidal/permeability-increasing protein (BPI) and calprotectin (MRP8/14) are antimicrobial peptides stored in leukocytes that act as effector molecules of the innate immune response. The purpose of this study was to determine whether parturition, premature rupture of the membranes (PROM) and microbial invasion of the amniotic cavity (MIAC) are associated with changes in amniotic fluid concentrations of these antimicrobial peptides. Study design: Amniotic fluid was retrieved by amniocentesis from 333 patients in the following groups: group 1, mid-trimester with a subsequent normal pregnancy outcome (n = 84); group 2, preterm labor and intact membranes without MIAC who delivered at term (n = 36), or prematurely (n = 52) and preterm labor with MIAC (n = 26); group 3, preterm PROM with (n = 26) and without (n = 26) MIAC; and group 4, term with intact membranes in the absence of MIAC, in labor (n = 52) and not in labor (n = 31). The concentrations of HNP 1-3, BPI and calprotectin in amniotic fluid were determined by specific and sensitive immunoassays. Placentae of patients in both preterm labor with intact membranes and preterm PROM groups who delivered within 72 h of amniocentesis were examined. Non-parametric statistics, receiver-operating characteristic (ROC) curves and Cox regression models were used for analysis. A p value of < 0.05 was considered statistically significant. Results: Intra-amniotic infection was associated with a significant increase in amniotic fluid concentrations of immunoreactive HNP 1-3, BPI and calprotectin in both women with preterm labor and intact membranes, and women with preterm PROM. Preterm PROM was associated with a significant increase in amniotic fluid concentrations of immunoreactive HNP 1-3, BPI and calprotectin. Preterm parturition was associated with a significant increase in amniotic fluid concentrations of immunoreactive HNP 1-3, BPI and calprotectin, while parturition at term was associated with a significant increase in amniotic fluid concentrations of immunoreactive HNP 1-3. Among patients with preterm labor and intact membranes, elevation of amniotic fluid HNP 1-3, BPI and calprotectin concentrations was associated with intra-amniotic inflammation, histological chorioamnionitis and a shorter interval to delivery. Conclusion: MIAC, preterm parturition and preterm PROM are associated with increased amniotic fluid concentrations of immunoreactive HNP 1-3, BPI and calprotectin. Moreover, elevated amniotic fluid concentrations of BPI, immunoreactive HNP 1-3 and calprotectin are associated with intra-amniotic inflammation, histological chorioamnionitis and shorter amniocentesis-to-delivery interval in patients presenting with preterm labor with intact membranes.

Alcohol use and pregnancy: Improving identification

Objective To test the effectiveness of a four-item prenatal-alcohol-use, self-administered screening questionnaire that asks about tolerance to alcohol, being annoyed by others comments about drinking, attempts to cut down, and having a drink first thing in the morning (“eye-opener”) (T-ACE) in an ethnically and socioeconomically diverse sample. Methods Two hundred fifty T-ACE-positive and 100 T-ACE-negative women completed a comprehensive assessment of their alcohol use after initiating prenatal care at the Brigham and Womens Hospital in Boston, Massachusetts. This comprehensive assessment, which included the Alcohol Use Disorders Identification Test and the Short Michigan Alcoholism Screening Test as comparisons to the T-ACE, generated three criterion standards: Diagnostic and Statistical Manual of Mental Disorders, Third Ed., Revised (DSM-III-R), lifetime alcohol diagnoses, risk drinking (regularly having more than one fluid ounce of alcohol per drinking day before pregnancy), and current drinking. Results T-ACE-positive pregnant women were more likely than T-ACE-negative women to satisfy DSM-III-R criteria for lifetime alcohol diagnoses (40% versus 14%, P < .001) and risk drinking (39% versus 8%, P < .001) and to have current alcohol consumption (43% versus 13%, P < .001). In contrast, obstetric staff members documented only 33 (9%) women as using alcohol at any time, even though nearly all subjects (96%) were asked about drinking upon initiation of prenatal care. Conclusion The T-ACE was the most sensitive screen for lifetime alcohol diagnoses, risk drinking, and current alcohol consumption. It outperformed obstetric staff assessment of any alcohol use by pregnant women enrolled in the study.

A brief intervention for prenatal alcohol use An in-depth look

About 20% of pregnant women will drink alcohol, even though no universally safe level of prenatal alcohol consumption has been established. This study of 123 alcohol screen-positive pregnant women receiving a brief intervention in the 16th week of gestation examines the relationship of drinking goals, reasons for the goals, recognition of situations increasing risk of drinking, and subsequent antepartum consumption. While women who named abstinence as their antepartum drinking goal were more likely not to be consuming alcohol at the time of study enrollment (chi(2) = 16.80, df = 1, p =.001), current drinkers who named abstinence as their goal did reduce subsequent prenatal alcohol use (chi(2) = 10.04, df = 1, p =.002). All current drinkers who indicated fetal alcohol syndrome as a reason not to drink reduced their subsequent alcohol consumption (chi(2) = 11.04, df = 1, p =.001). Future efforts may include the partners and support systems of pregnant women in education or intervention programs to reduce prenatal alcohol consumption to enhance their effectiveness.

Evidence of in vivo generation of thrombin in patients with small-for-gestational-age fetuses and pre-eclampsia.

Objective: Thrombotic lesions in the maternal or fetal compartments are frequently observed in the placentas of patients with small-for-gestational-age (SGA) fetuses and in pre-eclampsia. The objective of this study was to determine whether there was evidence of in vivo generation of thrombin, the ratelimiting enzyme responsible for the formation of fibrin. The plasma concentrations of thrombin-antithrombin (TAT) complexes were used as an index of thrombin generation. Methods: TAT complexes were measured in the plasma from 68 women from the following groups: normal pregnancy (n = 29); pre-eclampsia (n = 26); and SGA (defined as estimated fetal weight below the 10th centile for gestational age, which was confirmed by neonatal birth weight) (n = 13). TAT complex plasma concentrations were determined with a specific and sensitive immunoassay. Statistical analysis was performed with non-parametric statistics. Results: The median plasma TAT complex concentrations were significantly higher in patients who delivered SGA neonates than in normal pregnant women (SGA, median 24.2 μg/l; range 11.9-788.7 vs. normal pregnancy, median: 14.4 μg/l; range 6.8-26.9; p = 0.001). Patients with pre-eclampsia had a higher median plasma TAT complex concentration than normal pregnant women (pre-eclampsia, median 18.1 μg/l; range 10.0-75.2 vs. normal pregnancy, median 14.4 μg/l; range 6.8-26.9; p = 0.02). Conclusion: In vivo generation of thrombin, determined by the plasma concentrations of TAT complexes, is higher in patients with SGA fetuses and patients with pre-eclampsia than in normal pregnancy.

Age-Related Increases in Long-Range Connectivity in Fetal Functional Neural Connectivity Networks In Utero

Highlights • We examined patterns of connectivity in human fetal brain networks.• The fetal brain demonstrates cerebral-cerebellar and cortical-subcortical connectivity.• Many forms of cerebral connectivity are present by the third trimester.• Default mode network connections were evident in fetuses older than 35 weeks.• Long-range functional connectivity is more prominent in older fetuses.

Intrinsic functional brain architecture derived from graph theoretical analysis in the human fetus.

The human brain undergoes dramatic maturational changes during late stages of fetal and early postnatal life. The importance of this period to the establishment of healthy neural connectivity is apparent in the high incidence of neural injury in preterm infants, in whom untimely exposure to ex-uterine factors interrupts neural connectivity. Though the relevance of this period to human neuroscience is apparent, little is known about functional neural networks in human fetal life. Here, we apply graph theoretical analysis to examine human fetal brain connectivity. Utilizing resting state functional magnetic resonance imaging (fMRI) data from 33 healthy human fetuses, 19 to 39 weeks gestational age (GA), our analyses reveal that the human fetal brain has modular organization and modules overlap functional systems observed postnatally. Age-related differences between younger (GA <31 weeks) and older (GA≥31 weeks) fetuses demonstrate that brain modularity decreases, and connectivity of the posterior cingulate to other brain networks becomes more negative, with advancing GA. By mimicking functional principles observed postnatally, these results support early emerging capacity for information processing in the human fetal brain. Current technical limitations, as well as the potential for fetal fMRI to one day produce major discoveries about fetal origins or antecedents of neural injury or disease are discussed.

Identifying prenatal alcohol use: screening instruments versus clinical predictors.

The purpose of this study is to compare the accuracy of screening instruments with clinical predictors in the identification of prenatal alcohol use. 350 women initiating prenatal care at the Brigham and Womens Hospital (Boston, MA) completed the T-ACE, AUDIT, and SMAST. The predictive accuracy of each was compared using Receiver Operating Characteristic (ROC) curve analysis. The T-ACE, AUDIT, and clinical predictors alone correctly identified 65 to 70% of current drinkers, whereas the SMAST alone performed only slightly better than chance. The predictive ability of the T-ACE was further improved with the addition of clinical predictors.

Racial differences in the predictive value of the TDx fetal lung maturity assay.

OBJECTIVE Black newborns have lower rates of neonatal respiratory distress syndrome compared with nonblack newborns. This has been attributed to accelerated lung maturation. Previous studies have demonstrated a difference in the predictive value of the lecithin/sphingomyelin ratio, a test for lung maturity, between races. Our study examines the predictive value of the newer TDx Fetal Lung Maturity Surfactant-to-Albumin assay. STUDY DESIGN We reviewed the records of 393 nonblack and 87 black infants delivered within 72 hours of the TDx FLM S/A assay testing. We compared the rates of neonatal respiratory distress syndrome by race, stratified by results. RESULTS In our study population black newborns had less than one half the rate of respiratory distress syndrome compared with nonblack newborns (4.6% vs 10.4%). To adjust for possible differences in the timing of lung maturation, the results were stratified by the TDx FLM S/A assay result. Black race had a protective effect (Mantel-Haenszel weighted odds ratio 0.30, 95% confidence interval 0.06 to 0.93, p < 0.05). This significant racial difference remained when both TDx FLM S/A assay result and gestational age were controlled in a multiple logistic regression analysis. CONCLUSIONS There are differences in the predictive value of the TDx FLM S/A assay among races. Black fetuses are less likely to have respiratory distress syndrome. The difference in rates of respiratory distress syndrome between races must be due to either a qualitative difference in the surfactant or to an anatomic difference in fetal lungs. Consideration should be given to a lower cutoff value for a mature test result in black women.

The effect of gestational age on trial of labor after Cesarean section

Objectives: To evaluate the effect of gestational age on the rate of successful vaginal delivery and the rate of uterine rupture in patients undergoing a trial of labor (TOL) after a prior Cesarean delivery.Study design: This was a cohort study including patients with a live singleton fetus undergoing a TOL after a previous low transverse Cesarean delivery between 1988 and 2002. Patients were divided into three groups according to gestational age: 24–36 weeks 6 days, 37–40 weeks 6 days and ≥41 weeks. Obstetric outcomes, including the rates of successful vaginal delivery and symptomatic uterine rupture, were compared between the groups. Multivariate logistic regression analysis was performed to adjust for potential confounding factors.Results: There were 253, 1911 and 329 patients in each group, respectively. In patients with advanced gestational age (≥41 weeks) the rate of uterine rupture was significantly higher (0% vs. 1.0% vs. 2.7%, p=0.006) and the rate of successful vaginal deliveries was significantly lower (83% vs. 76.9% vs. 62.6%, p<0.001). After adjusting for confounding variables, advanced gestational age was associated with a lower rate of successful vaginal delivery (odds ratio 0.68, 95% CI 0.51–0.89), and a higher rate of uterine rupture (odds ratio 2.85, 95% CI 1.27–6.42) when compared to 37–40 weeks 6 days.Conclusion: Advanced gestational age is associated with higher rates of failed TOL and uterine rupture.

Weak functional connectivity in the human fetal brain prior to preterm birth

It has been suggested that neurological problems more frequent in those born preterm are expressed prior to birth, but owing to technical limitations, this has been difficult to test in humans. We applied novel fetal resting-state functional MRI to measure brain function in 32 human fetuses in utero and found that systems-level neural functional connectivity was diminished in fetuses that would subsequently be born preterm. Neural connectivity was reduced in a left-hemisphere pre-language region, and the degree to which connectivity of this left language region extended to right-hemisphere homologs was positively associated with the time elapsed between fMRI assessment and delivery. These results provide the first evidence that altered functional connectivity in the preterm brain is identifiable before birth. They suggest that neurodevelopmental disorders associated with preterm birth may result from neurological insults that begin in utero.