Prospective research on infants with mild encephalopathy: the PRIME study.

OBJECTIVE: To determine short-term outcomes of infants with evidence of hypoxia-ischemia at birth and classified as mild neonatal encephalopathy (NE) at <6 h of age. STUDY DESIGN: Prospective multicenter study. Mild NE was defined as ⩾1 abnormal category in modified Sarnat score. Primary outcome was any abnormality on early amplitude integrated electroencephalogram (aEEG) or seizures, abnormal brain magnetic resonance imaging (MRI) or neurological exam at discharge. RESULTS: A total of 54/63 (86%) of enrolled infants had data on components of the primary outcome, which was abnormal in 28/54 (52%): discontinuous aEEG (n=4), MRI (n=9) and discharge exam (n=22). Abnormal tone and/or incomplete Moro were the most common findings. MRI abnormalities were confined to cerebral cortex but two infants had basal ganglia and/or thalamus involvement. The 18 to 24 months follow-up is ongoing. CONCLUSIONS: A larger than expected proportion of mild NE infants with abnormal outcomes was observed. Future research should evaluate safety and efficacy of neuroprotection for mild NE.

Ganciclovir population pharmacokinetics in neonates following intravenous administration of ganciclovir and oral administration of a liquid valganciclovir formulation.

Cytomegalovirus (CMV) is the most common viral congenital infection, producing both sensorineural hearing loss and mental retardation. Our objective was to assess the population pharmacokinetics of a research-grade oral valganciclovir solution in neonates with symptomatic congenital CMV disease. Twenty-four neonates received 6 weeks of antiviral therapy. Ganciclovir and valganciclovir were measured by liquid chromatography/tandem mass spectroscopy. NONMEM version VI beta was used for population analyses. All profiles were consistent with a one-compartment model. Postnatal age, body surface area, and gender did not improve the model fit after body weight was taken into account. The typical value of clearance (l/h), distribution volume (l), and bioavailability of ganciclovir were 0.146 x body weight (WT)(1.68), 1.15 x WT, and 53.6%, respectively. Although these results cannot be extrapolated to extemporaneously compounded valganciclovir preparations, they provide the foundation on which a commercial-grade valganciclovir oral solution may be a viable option for administration to neonates.

Congenital syphilis in neonates with nonreactive nontreponemal test results.

OBJECTIVE: Infants whose mothers had syphilis during pregnancy were studied to determine how often exposed newborns with normal physical examinations and nonreactive nontreponemal serologic tests had abnormal laboratory or radiographic studies. STUDY DESIGN: Retrospective analysis of prospectively collected data from infants born to mothers with syphilis and had a normal examination and a nonreactive nontreponemal test. Some infants had IgM immunoblotting, PCR testing or rabbit infectivity testing (RIT) performed. RESULTS: From 1984 to 2002, 115 infants had a nonreactive serum Venereal Disease Research Laboratory (VDRL)/rapid plasma reagin (RPR) test and a normal physical examination at birth. Among 87 infants born to mothers who had untreated syphilis, 4 had a positive serum IgM immunoblot or PCR test, but none had spirochetes recovered by RIT. Two infants had anemia, one had an elevated serum alanine aminotransferase concentration and one with Down's syndrome had direct hyperbilirubinemia. Among 14 infants born to mothers treated <4 weeks before delivery, none had abnormal laboratory or radiographic tests, although 1 of 11 had a reactive serum IgM immunoblot. Among 14 infants born to mothers treated ⩾4 weeks before delivery, none had abnormal laboratory or radiographic tests. CONCLUSION: Newborns with normal physical examination and nonreactive nontreponemal test results are unlikely to have abnormalities detected on conventional laboratory and radiographic testing.

Barriers to enrollment in a randomized controlled trial of hydrocortisone for cardiovascular insufficiency in term and late preterm newborn infants.

OBJECTIVE: To analyze reasons for low enrollment in a randomized controlled trial (RCT) of the effect of hydrocortisone for cardiovascular insufficiency on survival without neurodevelopmental impairment (NDI) in term/late preterm newborns. STUDY DESIGN: The original study was a multicenter RCT. Eligibility: ⩾34 weeks' gestation, <72 h old, mechanically ventilated, receiving inotrope. Primary outcome was NDI at 2 years; infants with diagnoses at high risk for NDI were excluded. This paper presents an analysis of reasons for low patient enrollment. RESULTS: Two hundred and fifty-seven of the 932 otherwise eligible infants received inotropes; however, 207 (81%) had exclusionary diagnoses. Only 12 infants were randomized over 10 months; therefore, the study was terminated. Contributing factors included few eligible infants after exclusions, open-label steroid therapy and a narrow enrollment window. CONCLUSION: Despite an observational study to estimate the population, very few infants were enrolled. Successful RCTs of emergent therapy may require fewer exclusions, a short-term primary outcome, waiver of consent and/or other alternatives.

Seasonal and lactational changes in mineral composition of milk from Iberian red deer (Cervus elaphus hispanicus).

Milk minerals are important for calf growth, and they have other roles as well, such as immune regulation. This 2-yr study examined content of Ca, P, Mg, Na, K, Fe, and Zn in milk of 54 Iberian red deer hinds through 18 wk of lactation. Mean mineral composition of fresh milk was ash = 1.168 +/- 0.007%, Ca = 2,330 +/- 20 mg/kg, P = 640 +/- 10 mg/kg, K = 1,100 +/- 10 mg/kg, Na = 385 +/- 3 mg/kg, Mg = 138 +/- 1 mg/kg, Zn = 12.5 +/- 0.2 mg/kg, and Fe = 0.65 +/- 0.03 mg/kg. All minerals except Mg varied by week of lactation, but variation was usually <10% except for Fe (83% variation) and Zn (30% variation); both of those minerals increased as lactation proceeded. Increased concentrations of Fe and Zn in later lactation compensated for the reduction in milk production in mid and late lactation such that daily production was less variable for Fe (55% variation) or Zn (79% variation) than for other minerals (118 to 135% variation). Potassium content of milk decreased across time, but that effect occurred primarily during the last few weeks of lactation. Calving later vs. early in the calving season had variable effects on concentrations of different minerals: P, Mg, and K concentrations were not affected; Ca, Mg, and Na were all lower in milk from later calving hinds; and both Fe and Zn had higher concentrations in milk from hinds that calved later in the season. Lactating hinds seem to maintain a more stable daily yield of the microminerals Fe and Zn in milk compared with more variable concentrations of macrominerals as lactation progresses. Because of the essential role of Fe and Zn in immune function, a more stable supply of those minerals might be important to the health of growing red deer calves.

Revised reference ranges for circulating neutrophils in very-low-birth-weight neonates.

OBJECTIVE: Healthy very-low-birth-weight neonates (VLBW, < or = 1500 g) exhibit a high incidence of neutropenia according to Manroe's reference ranges for neutrophil indices. Since these reference ranges may be inappropriate for VLBW neonates, we determined the reference ranges for circulating peripheral neutrophils in VLBW neonates between birth and 28 days of age. METHODS: Serial, timed peripheral white blood cell counts (n = 1788) were prospectively obtained between birth and 28 days from 193 inborn, VLBW neonates delivered between January 1 and December 31, 1990. Data were divided into neutrophil counts obtained prior to (n = 630) and after (n = 1158) 60 hours of age. After excluding counts from neonates with perinatal and/or neonatal complications, values from "normal" neonates were compared to Manroe's reference ranges. Where indicated new ranges were developed. RESULTS: Although immature neutrophil (ATI) and immature:total neutrophil (I:T) values were within Manroe's reference ranges (P > .1) throughout the neonatal period, 67% of total neutrophil values (ATN) obtained prior to 60 hours of age were outside (P < .001) and 95% were considered neutropenic. Newly developed ATN reference ranges for VLBW neonates have a wider range of distribution compared to Manroe's results, primarily reflecting a decrease in the lower boundary. ATN values between 61 hours and 28 days also differed (P < .001), and new ranges had upper and lower boundaries of 6000 and 1100/mm3, respectively. Maternal hypertension was associated with neonatal neutropenia (P < .001) without abnormalities of ATI or I:T prior to day 3 of life; however, neutrophilia predominated after day 7. Between birth and 28 days > 70% of ATN values were abnormal in neonates with apnea, neutrophilia occurring in > 90% of counts; I:T values, however, were normal between 61 hours and 28 days. CONCLUSIONS: Normal preterm VLBW neonates have ATN reference ranges that differ significantly from that for larger, older neonates, demonstrating the effects of development on neutrophil dynamics. The predictability of neonatal infection using these new reference ranges requires additional study.

Effect of maternal hypertension on neonatal neutropenia and risk of nosocomial infection.

Neonatal neutropenia occurs in approximately 50% of newborns delivered by women with pregnancy-induced hypertension. It is thought to be transient, independent of birth weight and gestational age, and unassociated with significant risks, including infection. It recently was suggested that neonatal neutropenia occurs primarily in smaller, younger neonates, is related to the severity of pregnancy-induced hypertension, and importantly, may be associated with an increased risk for nosocomial infection. We examined these points in a large inborn population in consecutive years, performing retrospective (n = 110, 1989) and prospective (n = 151, 1990) studies in low birth weight (less than or equal to 2200 g) neonates delivered by women with pregnancy-induced hypertension. Overall, 40% to 50% of neonates studied developed neonatal neutropenia, and they were younger and smaller (P less than .01) than non-neutropenic neonates. In the prospective study, neutropenic neonates were more likely to have mothers with severe pregnancy-induced hypertension (P less than .001), and the incidence of neonatal neutropenia was primarily among neonates less than 30 weeks of gestation and less than 1500 g birth weight, approximately 80% vs 35% to 45% in older, larger neonates or infants (P less than .001). Although nosocomial infection occurred more frequently among the group of neutropenic neonates in the prospective study (P less than .02), the incidence was similar to that in matched non-neutropenic controls delivered of normotensive women. Thrombocytopenia (less than 100,000/mm3) was not more frequent in neutropenic neonates.(ABSTRACT TRUNCATED AT 250 WORDS)

Vertical transmission of Ureaplasma urealyticum from mothers to preterm infants.

Ureaplasma urealyticum is a common component of the vaginal flora during pregnancy. Although colonization of low birth weight infants with U. urealyticum occurs frequently, the actual rate of vertical transmission of U. urealyticum in preterm infants has not been determined. Sixty-five preterm infants (less than 37 weeks of gestation) born to mothers colonized with U. urealyticum had eye, throat, vagina and rectum cultured for U. urealyticum at 1, 3 and 7 days of age and weekly thereafter for the first month of life while the infants remained in the hospital. Thirty-eight infants (58%) had at least one culture site positive for U. urealyticum (eye, 8%; throat, 37%, vagina, 54%; and rectum, 18%). Vertical transmission was not affected by method of delivery or duration of rupture of amniotic membranes. The rate of vertical transmission of U. urealyticum was higher among infants with birth weight less than 1,000 g (89%) than among those with birth weight of 1,000 g or greater (54%) (P = 0.07). Chronic lung disease developed in 9 of the 65 (14%) infants; 8 were colonized with U. urealyticum. The high rate of ureaplasmal colonization and chronic lung disease in infants less than 1,000 g makes these infants a suitable target population for a clinical treatment trial to determine whether eradication of U. urealyticum would decrease the incidence of chronic lung disease.

Vertical transmission of Ureaplasma urealyticum in full term infants.

Ureaplasma urealyticum is a common inhabitant of the urogenital tract of pregnant women. Although colonization of newborn infants with U. urealyticum has been documented previously, the actual rate of vertical transmission has not been determined. Cervical cultures for U. urealyticum were performed on 1315 pregnant women on admission to the labor suite. A positive culture was found in 810 (62%). Eye, nasopharyngeal and/or throat, vaginal and rectal cultures were obtained in the first 5 days of life from 132 full term infants born to mothers colonized with U. urealyticum. Fifty-nine infants (45%) had at least one culture site positive for U. urealyticum (eye, 4%; nasopharynx 24%; throat, 16%; vagina, 53%; and rectum, 9%). None of the infants had evidence of disease caused by U. urealyticum during the nursery stay. Vertical transmission was not affected by the method of delivery. However, among the vaginally delivered infants, rupture of membranes greater than 1 hour correlated with an increased rate of vertical transmission of U. urealyticum (52%) compared with rupture of membranes less than or equal to 1 hour (22%) (P less than 0.05). Because vertical transmission of U. urealyticum occurs frequently, caution must be exercised when attributing disease to U. urealyticum based solely on positive cultures of mucosal surfaces.

Ureaplasma urealyticum colonization and chronic lung disease in low birth weight infants.

Ureaplasma urealyticum is a common component of the vaginal flora during pregnancy. Transmission of U. urealyticum to the low birth weight infant may contribute to neonatal respiratory disease. We studied prospectively 111 infants with birth weights of 2 kg or less who were consecutively admitted to a neonatal intensive care unit during a 7-month period. The infants had eye, throat, vagina and/or rectum cultured for U. urealyticum on days 1, 3 and 7 and weekly thereafter until the time of discharge. Forty-six infants (41%) had at least one culture site positive for U. urealyticum (eye, 9%; throat, 35%; vagina, 34%; and rectum, 13%). Respiratory distress at birth was not associated with U. urealyticum colonization. However, colonization with U. urealyticum was significantly associated with the development of chronic lung disease. Of the infants colonized with U. urealyticum 30% developed chronic lung disease, whereas 8% of those not colonized developed chronic lung disease (P less than 0.05). Duration of positive pressure ventilation and oxygen therapy could not account for the higher incidence of chronic lung disease in the infants colonized with U. urealyticum. Stepwise logistic regression analysis using the profiles of birth weight, need for intubation and status of colonization with U. urealyticum correctly identified 79% of the infants who developed chronic lung disease. Additional studies serologic techniques are needed to confirm the association of U. urealyticum colonization and chronic lung disease in low birth weight infants.

Elevated cytokine concentrations in the nasopharyngeal and tracheal secretions of children with respiratory syncytial virus disease.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract disease in infants. The role of inflammatory mediators in the pathogenesis of RSV disease is not well-understood. The present study was designed (1) to determine whether RANTES (regulated on activation, normal T cell expressed and presumably secreted), macrophage-inflammatory protein-1-alpha (MIP-1-alpha), interleukin (IL)-6, IL-8 and IL-10 can be detected in respiratory secretions of children with RSV infection and (2) to assess whether the concentrations of these cytokines in respiratory secretions correlate with white blood cell (WBC) counts and RSV concentrations and with disease severity. METHODS: During the 1996 to 1997 RSV season, we studied prospectively 14 intubated and 14 nonintubated children hospitalized with RSV disease. Nasal wash (NW) and tracheal aspirate (TA) samples were obtained from intubated patients on Hospital Days 1, 3 and 5. NW samples were obtained from nonintubated patients on hospital days 1 and 3. Seven healthy children undergoing elective surgery served as controls. All samples were analyzed for: (1) WBC and differential counts; (2) concentrations of RANTES, MIP-1-alpha, IL-6, IL-8 and IL-10; and (3) quantitative RSV cultures, except in control patients. RESULTS: RANTES, MIP-1-alpha, IL-6, IL-8 and IL-10 were detected in NW and TA samples from all children with RSV infection. The concentrations of these cytokines in samples obtained from children with RSV infection were significantly greater than those in samples obtained from control children. NW WBC counts significantly correlated with NW RANTES, IL-6, IL-8 and IL-10 concentrations, whereas TA WBC counts significantly correlated with TA IL-6, IL-8, IL-10 and MIP-1-alpha concentrations. NW RSV concentrations correlated with NW WBC counts and with NW cytokine concentrations. Among children with RSV infection nonintubated patients had greater NW WBC counts and NW RANTES concentrations than intubated patients. TA RANTES, IL-8 and IL-10 concentrations inversely correlated with clinical markers of RSV disease severity. CONCLUSION: The presence of cytokines in NW and TA samples of children with RSV infection suggests that they have a role in mediating the respiratory tract inflammation induced by RSV. These observations could have implications for designing new therapeutic strategies directed at immunomodulation of RSV disease.

Safety and pharmacokinetics of an intramuscular humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia. The MEDI-493 Study Group.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory disease in infants and children. MEDI-493 (palivizumab, Synagis) is a humanized monoclonal IgG1 antibody to the fusion protein of RSV, and it is highly active in vitro against RSV A and B strains. OBJECTIVE: To describe the safety, tolerance, immunogenicity and pharmacokinetics of monthly intramuscular injections of MEDI-493 among premature infants and children with bronchopulmonary dysplasia and to compare these data with information previously obtained with intravenous dosing. DESIGN: A Phase I/II multicenter, open label, escalating dose clinical trial. PATIENT POPULATION AND DOSING REGIMEN: Children (n=65) born prematurely at < or =35 weeks of gestation who were < or =6 months of age (n=41) and children with bronchopulmonary dysplasia who were < or =24 months of age (n=24) were enrolled. From 1 to 5 monthly injections were given at doses of 5 mg/kg (n=11), 10 mg/kg (n=6) and 15 mg/kg (n=48). Serum was collected before administration of each dose, 30 days after the last dose, and 2, 7 and 14 days after the first and second doses for measurement of MEDI-493 concentrations by enzyme-linked immunosorbent assay. RESULTS: The pharmacokinetics of MEDI-493 were similar to those of other human IgG1 antibodies. Mean serum MEDI-493 concentrations were 91.1 microg/ml (range, 52.3 to 174.0) 2 days after the initial dose of 15 mg/kg and 49.2 microg/ml (range, 13.5 to 132.0) at 30 days. Monthly dosing of 15 mg/kg maintained mean trough concentrations of approximately 70 microg/ml. These concentrations were similar to previously published trough concentrations after i.v. administration. MEDI-493 injections were well-tolerated. Only three children had adverse events judged to be possibly related to MEDI-493. Ten children had transient, low titer anti-MEDI-493 binding titers (1:10 to 1:40) which were not associated with a pattern of specific adverse events or alterations of MEDI-493 concentrations. Two patients in the 5-mg/kg dose group were hospitalized for RSV; no RSV hospitalizations were found in the higher dose groups. CONCLUSIONS: MEDI-493 was safe and well-tolerated. Monthly intramuscular doses of 15 mg/kg maintained mean trough serum concentrations that were above 40 microg/ml (the value associated with 99% reduction of pulmonary RSV in the cotton rat model). These concentrations were similar to those previously reported with i.v. administration of MEDI-493.

Safety, tolerance and pharmacokinetics of a humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia. MEDI-493 Study Group.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants. MEDI-493 (palivizumab) is a humanized monoclonal antibody to the fusion protein of RSV and is active in animal models for prevention of pulmonary RSV replication. OBJECTIVE: To describe the safety, tolerance, immunogenicity and pharmacokinetics of repeat intravenous doses of MEDI-493 in premature infants or infants with bronchopulmonary dysplasia. DESIGN: Phase I/II multicenter, randomized, double blind, placebo-controlled, dose escalation trial. PATIENT POPULATION: Infants born prematurely (< or = 35 weeks of gestation) who were < or = 6 months of age and infants with bronchopulmonary dysplasia who were < or = 24 months of age were eligible for study participation. STUDY AGENTS: Participants received 3, 10 or 15 mg/kg MEDI-493 or 0.9% saline intravenously every 30 days for up to five doses. RESULTS: MEDI-493 was safe and well-tolerated and did not induce a specific anti-MEDI-493 response. The mean half-life of 20 days was comparable with that of other immunoglobulin G preparations. Mean trough serum concentrations 30 days after Infusion 1 were 6.8, 36.1 and 60.6 microg/ml for the 3-, 10- and 15-mg/kg dose groups, respectively. After Infusion 2 the trough concentrations were 11.9, 45.2 and 70.7 microg/ml. After subsequent doses the mean trough values ranged from 14 to 18 microg/ml in those given 3 mg/kg and were > 40 microg/ml for patients who received 10 or 15 mg/kg MEDI-493 (46 to 72 microg/ml and 88 to 96 microg/ml, respectively). CONCLUSIONS: MEDI-493 was safe and well-tolerated in this high risk pediatric population. Mean serum concentrations of MEDI-493 that have been shown to produce a 2-log reduction in pulmonary RSV titer in cotton rats were maintained when 10 or 15 mg/kg MEDI-493 was given every 30 days to pediatric patients at high risk for serious RSV disease. Monthly doses of 15 mg/kg maintained concentrations of > 40 microg/ml for the majority of patients.

Enzyme-linked immunosorbent assay to assess respiratory syncytial virus concentration and correlate results with inflammatory mediators in tracheal secretions.

OBJECTIVE: We developed an enzyme-linked immunosorbent assay (ELISA) for the quantitation of respiratory syncytial virus (RSV) in respiratory secretions in intubated patients infected with RSV. METHODS: We compared the quantitative ELISA and a standardized plaque assay in intubated children <2 years of age who were mechanically ventilated for severe RSV disease and enrolled in a randomized double blind placebo-controlled treatment trial of a monoclonal antibody to the F protein of RSV (palivizumab; Synagis). We also examined the relationship between the concentrations of virus as measured by ELISA and of three inflammatory indices in respiratory secretions (white blood cell count, myeloperoxidase and eosinophilic cationic protein). RESULTS: Quantitative ELISA and plaque assay were highly correlated for both tracheal aspirates (r = 0.67, P = 0.001) and nasal wash specimens (r = 0.75, P = 0.001). Treatment with palivizumab significantly neutralized RSV in tracheal aspirates as measured by plaque assay. In contrast quantitation of RSV by ELISA was not affected by palivizumab treatment. This finding is consistent with results that were obtained in preliminary studies of RSV-containing media treated with monoclonal antibody, where we found that the ELISA measured virus whether antibody-bound or not. The inflammatory indices were not correlated with RSV concentration measured by ELISA or plaque assay. CONCLUSIONS: We conclude that this quantitative ELISA is a potentially useful tool for measurement of RSV concentration in respiratory secretions that may help elucidate the pathophysiology of acute RSV infection. Specific antiviral strategies for the treatment of RSV disease could be evaluated by this method.

Safety of the concomitant use of caspofungin and cyclosporin A in patients with invasive fungal infections.

Caspofungin, an echinocandin antifungal agent, is active against invasive Aspergillus and Candida infections. In a phase I study in healthy volunteers, mild transient increases in serum aminotransferases were observed with the concomitant administration of caspofungin and cyclosporin A (CsA). As a result, it is recommended that the concomitant use of the two drugs be limited to those settings with appropriate risk-benefit balance. We retrospectively assessed safety data in 14 patients with refractory invasive mycoses who were treated concomitantly with CsA and caspofungin before the drug was licensed in Spain. In all, 13 patients were adults (median age, 31.5 years; range, 14-67 years). The average duration of concomitant therapy was 15 days (range, 2-43 days). No clinically significant elevations of serum aminotransferases were observed, and no patient had concomitant therapy discontinued or interrupted due to a drug-related adverse event. In this study of a limited number of patients, the coadministration of caspofungin and CsA was generally well tolerated.

Acyclovir suppression to prevent cesarean delivery after first-episode genital herpes.

OBJECTIVE: To determine if suppressive acyclovir therapy given to term gravidas experiencing a first episode of genital herpes simplex virus (HSV)-infection during pregnancy decreases the need for cesarean delivery for that indication. METHODS: Forty-six pregnant women with first episodes of genital herpes during pregnancy were randomly assigned to receive oral acyclovir 400 mg or placebo, three times per day, from 36 weeks' gestation until delivery as part of a prospective, double-blind trial. Herpes simplex virus cultures were obtained when patients presented for delivery. Vaginal delivery was permitted if no clinical recurrence was present; otherwise, a cesarean was performed. Neonatal HSV cultures were obtained and infants were followed-up clinically. RESULTS: None of the 21 patients treated with acyclovir and nine of 25 (36%) treated with placebo had clinical evidence of recurrent genital herpes at delivery (odds ratio [OR] 0.04, 95% confidence interval [CI] 0.002-0.745; P = .002). No woman treated with acyclovir had a cesarean for herpes, compared with nine of 25 (36%) of those treated with placebo (OR 0.04, CI 0.002-0.745; P = .002). No patient in either treatment group experienced asymptomatic genital viral shedding at delivery. No neonate had evidence of herpes infection or adverse effects from acyclovir. CONCLUSION: Suppressive acyclovir therapy reduced the need for cesarean for recurrent herpes in women whose first clinical episode of genital HSV occurred during pregnancy. Suppressive acyclovir treatment did not increase asymptomatic viral shedding and was not harmful to the term fetus.

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 syphilis: clinical and laboratory characteristics.

OBJECTIVE: To examine the pathophysiology of fetal syphilis and correlate hematologic, immunologic, and sonographic findings. METHODS: Twenty-four women with untreated syphilis during pregnancy were prospectively identified. Sonography with amniocentesis and percutaneous umbilical blood sampling were performed. Darkfield examination, rabbit infectivity testing, and polymerase chain reaction for detection of Treponema pallidum were performed on amniotic fluid. Hematologic and chemical testing of fetal blood was performed using standard techniques. Fetal antitreponemal IgM was detected by Western blot assay. Maternal syphilis was treated with 2.4 to 4.8 million units of benzathine penicillin G intramuscularly. Neonatal outcomes and signs of congenital syphilis were recorded. RESULTS: Six women had primary, 12 had secondary, and six had early latent syphilis. Sixty-six percent of fetuses (95% confidence interval [CI] 47%, 82%) had either congenital syphilis or detection of Treponema pallidum in amniotic fluid. Sixty-six percent had hepatomegaly, including three fetuses (12.5%, 95% CI 4%, 31%) with ascites. Fetal antitreponemal IgM was detected in three cases. Abnormal liver transaminases were found in 88% (CI 69%, 96%), anemia in 26% (CI 13%, 47%), and thrombocytopenia in 35% (CI 19%, 55%). Maternal treatment was successful in 83% (CI 64%, 93%). Risk of treatment failure was significantly increased when hepatomegaly and ascites were present (P =.01). CONCLUSION: Findings with fetal syphilis are similar to those of neonatal syphilis. We hypothesize that fetal transaminase elevation occurs early in the course of infection; hematologic abnormalities and hydrops occur later. Severity of disease may be associated with risk of treatment failure.

Identification of Treponema pallidum in amniotic fluid and fetal blood from pregnancies complicated by congenital syphilis.

Two pregnant women with secondary syphilis underwent amniocentesis and evaluation for fetal syphilis. In both cases, motile spirochetes, typical of Treponema pallidum, were observed during dark-field microscopic examination of the amniotic fluid. The presence of T pallidum was confirmed by antitreponemal monoclonal antibody immunofluorescence assays and by rabbit infectivity tests using the amniotic fluid. In the first case, an infant at 35 weeks' gestation delivered within 24 hours of amniocentesis had hepatosplenomegaly, osteochondritis, and neurosyphilis. In the second case, a fetus at 24 weeks' gestation was hydropic and a fetal blood sample showed anemia, thrombocytopenia, and elevated liver enzymes. Fetal syphilis was confirmed by rabbit infectivity testing using fetal blood obtained by funipuncture. This is the first report of the diagnosis of fetal syphilis by funipuncture and confirmation of the presence of virulent T pallidum in the blood of a human fetus. The mother was treated for secondary syphilis, but the infant had residual signs of congenital infection at birth 14 weeks later. Neonatal serum from the first case and fetal serum from the second case showed specific immunoglobulin M reactivity with the 47-kd antigen of T pallidum by Western blot assays. A new wild-type strain of T pallidum, designated DAL-1, was isolated from the amniotic fluid of the first case and is available for future studies. We conclude that the presence of T pallidum in amniotic fluid or fetal blood indicates fetal-placental infection. Further investigation is necessary to determine the pathogenesis of amniotic fluid infection and its role in the prenatal diagnosis of congenital syphilis.

Changes in angiotensin II receptors in dopamine-rich regions of the mouse brain with age and ethanol consumption.

The density of angiotensin II (Ang II) receptors was determined in three dopaminergic nerve terminal-rich brain regions (caudate putamen, nucleus accumbens, and ventral pallidum) of mice that were given either water (control) or 20% w/v ethanol (EtOH) to drink for either 2-8 weeks (young) or 46 weeks (old). The receptors were labeled with 125I-sarcosine1, isoleucine8 angiotensin II (125I-SI Ang II) and measured by quantitative densitometric image analysis (receptor autoradiography) or by saturation binding assays on homogenates of these brain regions. The selective AT2 receptor subtype antagonist PD 123319 (10 microM) was used to inhibit 125I-SI Ang II binding to AT2 receptors to determine AT1 receptor density in brain sections. In young control mice the density of Ang II receptor binding sites in the caudate putamen was 407+/-26 fmol/g, in the nucleus accumbens the density was 346+/-27 fmol/g, and in the ventral pallidum the density was 317+/-27 fmol/g. Less than 5% of specific 125I-SI Ang II binding was displaced by PD 123319, suggesting that nearly all of the Ang II receptors in these brain regions were the AT1 subtype. The Bmax in homogenates of these three regions in young control mice was 11.0+/-2.1 fmol/mg protein. The KD was 0.49+/-0.13. Ang II receptors in old mouse brains were decreased, respectively, by 32%, 35% and 30% in the caudate putamen, nucleus accumbens and ventral pallidum (p<0.001). Ang II receptors were slightly, but not significantly increased in both young and old EtOH-consuming mice.