James M. Alexander

A Randomized, Controlled Trial of Magnesium Sulfate for the Prevention of Cerebral Palsy

BACKGROUND Research suggests that fetal exposure to magnesium sulfate before preterm birth might reduce the risk of cerebral palsy. METHODS In this multicenter, placebo-controlled, double-blind trial, we randomly assigned women at imminent risk for delivery between 24 and 31 weeks of gestation to receive magnesium sulfate, administered intravenously as a 6-g bolus followed by a constant infusion of 2 g per hour, or matching placebo. The primary outcome was the composite of stillbirth or infant death by 1 year of corrected age or moderate or severe cerebral palsy at or beyond 2 years of corrected age. RESULTS A total of 2241 women underwent randomization. The baseline characteristics were similar in the two groups. Follow-up was achieved for 95.6% of the children. The rate of the primary outcome was not significantly different in the magnesium sulfate group and the placebo group (11.3% and 11.7%, respectively; relative risk, 0.97; 95% confidence interval [CI], 0.77 to 1.23). However, in a prespecified secondary analysis, moderate or severe cerebral palsy occurred significantly less frequently in the magnesium sulfate group (1.9% vs. 3.5%; relative risk, 0.55; 95% CI, 0.32 to 0.95). The risk of death did not differ significantly between the groups (9.5% vs. 8.5%; relative risk, 1.12; 95% CI, 0.85 to 1.47). No woman had a life-threatening event. CONCLUSIONS Fetal exposure to magnesium sulfate before anticipated early preterm delivery did not reduce the combined risk of moderate or severe cerebral palsy or death, although the rate of cerebral palsy was reduced among survivors. (ClinicalTrials.gov number, NCT00014989.)

Transfer of inflammatory cytokines across the placenta.

OBJECTIVE: The purpose of this study was to determine whether the placental transfer of interleukin (IL)-1α, IL-6, and tumor necrosis factor-α (TNF-α) occurs. METHODS: Four normal-term placentas were perfused for maternal–fetal transfer of the cytokines, 2 placentas for fetal–maternal transfer, and 4 additional placentas were used for an endogenous control. The ex vivo isolated cotyledon human placental perfusion model was used. The reference compound antipyrine was used to determine the transport fraction and clearance index of the cytokines. The cytokines were added to either the maternal or fetal circulations, and samples were collected for 1 hour in a constant-flow open circulation. Cytokine levels were compared between the study and control placentas. Concentrations of the cytokines were measured by sandwich enzyme immunoassay. RESULTS: The clearance index for the maternal–fetal transfer of IL-1α and TNF-α was 0.001, suggesting minimal transfer to the fetal circulation. The clearance index for IL-6 was 0.30, indicating transfer to the fetal circulation. When the cytokines were added to the fetal circulation, the clearance index for IL-1α was 0.001, again indicating minimal transfer. The clearance index for TNF-α in the fetal–maternal study was not determined. IL-6 had a clearance index of 0.23, which was similar to that observed with maternal–fetal transfer. IL-6 concentrations in the study placentas were higher than the concentrations found in the controls. CONCLUSION: There appears to be bidirectional transfer of IL-6 in the healthy-term human placental perfusion model. LEVEL OF EVIDENCE: II-2

Risk of hepatitis B transmission in breast-fed infants of chronic hepatitis B carriers☆

OBJECTIVE To measure the rate of hepatitis B (HBV) transmission from chronic HBV carriers to breast‐fed infants after immunoprophylaxis. METHODS Since 1992, information on women with HBV during pregnancy has been collected in a prospective longitudinal study. Those HBV carriers and their infants participating in a county HBV immunoprophylaxis program were identified. Infants were followed for up to 15 months and examined for hepatitis B infection by hepatitis B surface antigen (HBsAg). RESULTS A total of 369 infants born to women with chronic HBV met the inclusion criteria and received hepatitis B immune globulin at birth and the full course of the hepatitis B vaccine series. We compared 101 breast‐fed infants with 268 formula‐fed infants. There was no significant difference between the two groups with respect to the number of women who were positive for hepatitis B e antigen (HBeAg) (22% versus 26%, P = .51). Three women in the breast‐feeding group had liver transaminase abnormalities, compared with six women in the formula‐feeding group (P = .29). Overall, there were nine cases of HBV infection transmission (2.4%). None of the 101 breast‐fed infants and nine formula‐fed infants (3%) were positive for HBsAg after the initial vaccination series (P = .063). The mean length of time for breast‐feeding was 4.9 months (range 2 weeks to 1 year). CONCLUSION With appropriate immunoprophylaxis, including hepatitis B immune globulin and hepatitis B vaccine, breast‐feeding of infants of chronic HBV carriers poses no additional risk for the transmission of the hepatitis B virus.

Cesarean delivery: a randomized trial of epidural analgesia versus intravenous meperidine analgesia during labor in nulliparous women.

Background Controversy concerning increased cesarean births as a result of epidural analgesia for relief of labor pain has been attributed, in large part, to difficulties interpreting published studies because of design flaws. In this study, the authors compared epidural analgesia to intravenous meperidine analgesia using patient-controlled devices during labor to evaluate the effects of labor epidural analgesia, primarily on the rate of cesarean deliveries while minimizing limitations attributable to study design. Methods Four hundred fifty-nine nulliparous women in spontaneous labor at term were randomly assigned to receive either epidural analgesia or intravenous meperidine analgesia. Epidural analgesia was initiated with 0.25% bupivacaine and was maintained with 0.0625% bupivacaine and fentanyl 2 &mgr;g/ml at 6 ml/h with 5-ml bolus doses every 15 min as needed using a patient-controlled pump. Women in the intravenous analgesia group received 50 mg meperidine with 25 mg promethazine hydrochloride as an initial bolus, followed by 15 mg meperidine every 10 min as needed, using a patient-controlled pump. A written procedural manual that prescribed the intrapartum obstetric management was followed for each woman randomized in the study. Results A total of 226 women were randomized to receive epidural analgesia, and 233 women were randomized to receive intravenous meperidine analgesia. Protocol violations occurred in 8% (38 of 459) of women. There was no difference in the rate of cesarean deliveries between the two analgesia groups (epidural analgesia, 7% [16 of 226; 95% confidence interval, 4–11%]vs. intravenous meperidine analgesia, 9% [20 of 233; 95% confidence interval, 5–13%];P = 0.61). Significantly more women randomized to epidural analgesia had forceps deliveries compared with those randomized to meperidine analgesia (12% [26 of 226]vs. 3% [7 of 233];P < 0.001). Women who received epidural analgesia reported lower pain scores during labor and delivery compared with women who received intravenous meperidine analgesia. Conclusions Epidural analgesia compared with intravenous meperidine analgesia during labor does not increase cesarean deliveries in nulliparous women.

epidural Analgesia during Labor and Maternal Fever

Most studies indicate that epidural analgesia during labor is associated with maternal fever, although the nature of this fever is unclear. The consequences of maternal fever may include increased neonatal evaluations for sepsis, the increased use of antibiotics, and prolonged hospital stay. However, the need for such measures after epidural analgesia during labor is controversial. This article discusses currently held views on this issue.

Chorioamnionitis and the prognosis for term infants

OBJECTIVE To assess the effects of clinical chorioamnionitis and labor complications on short-term neonatal morbidity, including seizures. METHODS This was a retrospective cohort study of all live-born term infants who weighed more than 2500 g delivered between 1988 and 1997 at Parkland Memorial Hospital, Dallas, Texas. Infant outcomes were compared between women with and without clinical diagnoses of chorioamnionitis. Chorioamnionitis was based on maternal fever of 38C or greater with supporting clinical evidence including fetal tachycardia, uterine tenderness, and malodorous infant. RESULTS A total of 101,170 term infants were analyzed, 5144 (5%) of whom were born to women with chorioamnionitis. Apgar scores of 3 or less at 5 minutes, umbilical artery pH of 7.0 or less, delivery-room intubation, sepsis, pneumonia, seizures in the first 24 hours, and meconium aspiration syndrome were all increased in infants exposed to chorioamnionitis. After adjustment for confounding factors, including route of delivery and length of labor, chorioamnionitis remained significantly associated with intubation in the delivery room (odds ratio [OR] 2.0; 95% confidence interval [CI] 1.5, 2.6), pneumonia (OR 2.2; 95% CI 1.7, 2.8), and sepsis (OR 2.9; 95% CI 2.1, 4.1). Short-term neurologic morbidity, manifest as seizures, was not related to maternal infection during labor, but was significantly related to other labor complications. CONCLUSION The main short-term neonatal consequence of chorioamnionitis is infection. Short-term neurologic morbidity in infants is related to labor complications and not chorioamnionitis per se.

Efficacy of treatment for syphilis in pregnancy

OBJECTIVE To evaluate prospectively the Centers for Disease Control and Prevention (CDC) recommended regimens for the treatment of antepartum syphilis and prevention of congenital syphilis. METHODS This was a prospective evaluation of recommended syphilis treatment regimens from September 1, 1987, to August 31, 1989, at Parkland Memorial Hospital, Dallas, Texas. Women with syphilis were staged and treated according to CDC recommendations. Treatment included 2.4 million units of intramuscular (IM) benzathine penicillin G for primary, secondary, or early latent (less than 1 year) syphilis. Women with late latent (uncertain or longer than 1 year) syphilis were treated with 7.2 million units of benzathine penicillin G IM over 3 weeks. RESULTS During the study period, 448 of 28,552 women (1.6%) delivered were diagnosed with syphilis. One hundred eight were diagnosed at delivery and treated postpartum. The remaining 340 (75.9%) gravidas with untreated syphilis attending prenatal clinic comprised the study group. The success of therapy in preventing congenital syphilis was as follows: primary syphilis, 27 of 27; secondary syphilis, 71 of 75; early latent syphilis, 100 of 102; and late latent syphilis, 136 of 136. The success rate for all stages of syphilis was 334 of 340 (98.2%). The success rate of therapy in secondary syphilis was significantly different from that of the other groups (P = .03). Two of the six fetal treatment failures produced preterm stillborns. Only one maternal treatment failure occurred, in a human immunodeficiency virus-infected woman. CONCLUSION The CDC-recommended regimens for the prevention of congenital syphilis and treatment of maternal infection are effective, but the highest risk of fetal treatment failure exists with maternal secondary syphilis.

Fetal injury associated with cesarean delivery.

OBJECTIVE: To describe the incidence and type of fetal injury identified in women undergoing cesarean delivery. METHODS: Between January 1, 1999, and December 31, 2000, a prospective cohort study of all cesarean deliveries was conducted at 13 university centers. Information regarding maternal and infant outcomes was abstracted directly from hospital charts. RESULTS: A total of 37,110 cesarean deliveries were included in the registry, and 418 (1.1%) had an identified fetal injury. The most common injury was skin laceration (n=272, 0.7%). Other injuries included cephalohematoma (n=88), clavicular fracture (n=11), brachial plexus (n=9), skull fracture (n=6), and facial nerve palsy (n=11). Among primary cesarean deliveries, deliveries with a failed forceps or vacuum attempt had the highest rate of injuries (6.9%). In women with a prior cesarean delivery, the highest rate of injury also occurred in the unsuccessful trial of forceps or vacuum (1.7%), and the lowest rate occurred in the elective repeat cesarean group (0.5%). The type of uterine incision was associated with fetal injury, 3.4% “T” or “J” incision, 1.4% for vertical incision, and 1.1% for a low transverse (P=.003), as was a skin incision–to–delivery time of 3 minutes or less. Fetal injury did not vary in frequency with the type of skin incision, preterm delivery, maternal body mass index, or infant birth weight greater than 4,000 g. CONCLUSION: Fetal injuries complicate 1.1% of cesarean deliveries. The frequency of fetal injury at cesarean delivery varies with the indication for surgery as well as with the duration of the skin incision–to–delivery interval and the type of uterine incision. LEVEL OF EVIDENCE: II-3

The c-Myc-regulated microRNA-17~92 (miR-17~92) and miR-106a~363 clusters target hCYP19A1 and hGCM1 to inhibit human trophoblast differentiation.

ABSTRACT Mononuclear cytotrophoblasts of the human placenta proliferate rapidly, subsequently fuse, and differentiate to form multinucleated syncytiotrophoblast with induction of aromatase (hCYP19A1) and chorionic gonadotropin (hCGβ) expression. Using microarray analysis, we identified members of the miR-17∼92 cluster and its paralogs, miR-106a∼363 and miR-106b∼25, that are significantly downregulated upon syncytiotrophoblast differentiation. Interestingly, miR-19b and miR-106a directly targeted hCYP19A1 expression, while miR-19b also targeted human GCM1 (hGCM1), a transcription factor critical for mouse labyrinthine trophoblast development. Overexpression of these microRNAs (miRNAs) impaired syncytiotrophoblast differentiation. hGCM1 knockdown decreased hCYP19A1 and hCGβ expression, substantiating its important role in human trophoblast differentiation. Expression of the c-Myc proto-oncogene was increased in proliferating cytotrophoblasts compared to that in differentiated syncytiotrophoblast. Moreover, c-Myc overexpression upregulated miR-17∼92 and inhibited hCYP19A1 and hCGβ expression. Binding of endogenous c-Myc to genomic regions upstream of the miR-17∼92 and miR-106a∼363 clusters in cytotrophoblasts dramatically decreased upon syncytiotrophoblast differentiation. Intriguingly, we observed higher levels of miR-106a and -19b and lower aromatase and hGCM1 expression in placentas from preeclamptic women than in placentas from gestation-matched normotensive women. Our findings reveal that c-Myc-regulated members of the miR-17∼92 and miR-106a∼363 clusters inhibit trophoblast differentiation by repressing hGCM1 and hCYP19A1 and suggest that aberrant regulation of these miRNAs may contribute to the pathogenesis of preeclampsia.

Intensity of labor pain and cesarean delivery.

Some authors have suggested that the intensity of labor pain may be related to labor dystocia. We performed a secondary analysis of a previously published randomized investigation of the effects of epidural analgesia during labor compared with patient-controlled IV meperidine on cesarean delivery. Two-hundred-fifty-nine women who received patient-controlled IV meperidine were identified for analysis. All women were in spontaneous labor with a singleton, term gestation. Women requiring 50 mg or more of meperidine per hour during labor were compared with those who required <50 mg/h. In addition, their pain scores (visual analog scale) were compared before and after analgesia administration. Pain scores were significantly higher in women requiring 50 mg/h of meperidine (8.7 vs 8.0, P = 0.05), and their labors tended to be longer (9 vs 5 h, P = 0.09). More cesarean deliveries for obstructed labor were performed in women requiring >50 mg/h of meperidine (14% vs 1.4%, P = 0.001). Neonatal outcomes were similar in the two groups.