Staphylococcus aureus infections among children receiving a solid organ transplant: clinical features, epidemiology, and antimicrobial susceptibility.

BACKGROUND: Staphylococcus aureus is among the most common causes of healthcare-associated infection (HAI) in the United States. Patients who have received a solid organ transplant (SOT) represent a unique population for the acquisition of HAIs, given their preoperative organ failure, immunosuppression, and need for invasive procedures. However, limited literature is published on S. aureus infections among children with SOT. We describe the epidemiology, antimicrobial susceptibility, and clinical features of S. aureus infections among pediatric SOT recipients. DESIGN: An ongoing prospective S. aureus surveillance database from 2001 to 2012 was searched for infections in patients with a history of SOT at Texas Children's Hospital. Medical records and antibiotic susceptibility profiles were reviewed; specific attention was applied to the time since transplantation to infection. RESULTS: Out of the total of 696 transplants performed during the study period, 38 pediatric SOT recipients developed 41 S. aureus infections; the highest incidence of infection was among heart recipients. Overall, the most common infectious diagnoses were skin-and-soft-tissue infections (66.1%), followed by bacteremia (15.3%). Among isolates in SOT patients, 47.5%, 16.9%, and 6.7% were resistant to methicillin, clindamycin, or mupirocin, respectively. Three infections (7.3%) occurred in the early post-transplant period (<1 month), all of which were bacteremia (P = 0.007) and all caused by methicillin-susceptible S. aureus (MSSA). The majority of infections (90.2%) occurred in the late post-transplant period (>6 months). In 10 cases (16.9%), S. aureus infection was associated with graft rejection during the same admission. CONCLUSIONS: S. aureus represents an important cause of morbidity in pediatric SOT recipients. While the majority of infections occurred late after transplant (>6 months), those acquired in the early post-transplant period were more often invasive and caused by MSSA in our hospital. Physicians caring for SOT recipients should be aware of the risks posed by this pathogen and the potential concomitant morbidity including graft rejection.

Mycobacterium abscessus in cystic fibrosis lung transplant recipients: report of 2 cases and risk for recurrence.

Mycobacterium abscessus is increasingly recognized as an important pathogen in some individuals with advancing lung disease related to cystic fibrosis (CF). Because of its resistance to antimicrobial agents and virulence, its presence in the lungs of potential lung transplant recipients can be problematic. We present 2 cases of individuals with CF in whom M. abscessus was present in the preoperative sputum cultures. The organism manifested different degrees of invasiveness in the 2 cases after transplantation with different outcomes, suggesting an approach to future candidates for lung transplantation that may be of clinical significance to their physicians and surgeons.

The role of MR imaging in detecting nodal disease in thyroidectomy patients with rising thyroglobulin levels.

BACKGROUND AND PURPOSE: One of the dilemmas facing clinicians treating patients with thyroid cancer is the evaluation of postthyroidectomy patients with rising serum thyroglobulin levels and indeterminate or normal findings on neck sonography. In this study, we examine the role of MR imaging in this subgroup of patients. MATERIALS AND METHODS: We retrospectively reviewed MR images of patients with thyroid cancer with abnormal lymph nodes in the retropharyngeal and parapharyngeal spaces and determined the size and signal-intensity characteristics of these nodes. We reviewed patient charts for the following history: 1) thyroidectomy, 2) rising thyroglobulin levels, 3) iodine-131 radiation therapy, 4) neck dissection, and 5) pathology on neck sonography and chest CT. We reviewed pathology findings to determine if thyroid cancer metastases were present in these lymph nodes. RESULTS: Eight patients had abnormal retropharyngeal space nodes, and 1 patient had a parapharyngeal space mass. Lymph nodes ranged from 7 to 25 mm. On MR imaging, 1 patient had a cystic node, 2 had complex nodes, and 6 had solid nodes. Eight patients had rising serum thyroglobulin levels and a history of thyroidectomy, radioiodine therapy, and neck dissection. Two of these patients had no pathologic nodes on sonography and normal findings on chest CT. Six patients had tissue sampling of their skull base node, and metastatic thyroid cancer was present in 5. CONCLUSIONS: MR imaging of the neck should be considered in thyroidectomy patients with rising serum thyroglobulin levels and a history of radioiodine therapy and neck dissection. Radiologists should carefully examine the retropharyngeal and parapharyngeal spaces in these patients because nodal metastases may occur there more commonly than realized.

Pneumococcal infections in children after transplantation.

Bacterial infections in recipients of bone marrow and solid-organ transplants remain a major cause of morbidity and death. The cases of 42 children who had undergone transplantation and developed an infection with Streptococcus pneumoniae were retrospectively reviewed. Thirty-four patients had 1 episode of infection, whereas 7 had 2 episodes and 1 had 3 episodes of infection. Solid-organ recipients were more likely to have recurrent invasive disease (P<.02). A total of 31 (74%) of 42 patients were on immunosuppressive therapy, and 74% had been on antimicrobial therapy within 30 days before diagnosis of S. pneumoniae infection. Only 33% of eligible patients had received a pneumococcal vaccine. Twenty-six percent of isolates recovered were not susceptible to penicillin, and 18% were not susceptible to ceftriaxone. Two patients experienced infection-related deaths; one of these had a penicillin-nonsusceptible isolate. The antimicrobial susceptibilities and outcome of infections with S. pneumoniae in patients who have undergone transplantation are similar to those in the general pediatric population.

The differential roles of LFA-1 and Mac-1 in host defense against systemic infection with Streptococcus pneumoniae.

Mice deficient in CD18, which lack all four CD11 integrins, have leukocytosis and increased susceptibility to bacterial infection. To determine the effect of deficiencies in LFA-1 (CD11a/CD18) or Mac-1 (CD11b/CD18) on host defense against systemic bacterial infection, knockout mice were inoculated i.p. with Streptococcus pneumoniae. Increased mortality occurred in both LFA-1(-/-) (15 of 17 vs 13 of 35 in wild type (WT), p < 0.01) and Mac-1(-/-) (17 of 34 vs 6 of 25, p < 0.01) mice. All deaths in LFA-1(-/-) mice occurred after 72 h, whereas most deaths in Mac-1(-/-) mice occurred within 24-48 h. At 24 h, 21 of 27 Mac-1(-/-) mice were bacteremic, vs 15 of 25 WT (p = 0.05); no difference was observed between LFA-1(-/-) and WT. Increased bacteria were recovered from Mac-1(-/-) spleens at 2 h (p = 0.03) and 6 h (p = 0.002) and from livers (p = 0.001) by 6 h. No difference was observed at 2 h in LFA-1(-/-) mice, but by 6 h increased bacteria were recovered from spleens (p = 0.008) and livers (p = 0.04). Baseline and peak leukocyte counts were similar between Mac-1(-/-) and WT, but elevated in LFA-1(-/-). At 8 h, peritoneal neutrophils were increased in Mac-1(-/-), but not significantly different in LFA-1(-/-). Histopathologically, at 24 h Mac-1(-/-) animals had bacteremia and lymphoid depletion, consistent with sepsis. LFA-1(-/-) mice had increased incidence of otitis media and meningitis/encephalitis vs WT at 72 and 96 h. Both Mac-1 and LFA-1 play important but distinct roles in host defense to S. pneumoniae.

Outcome of invasive infections outside the central nervous system caused by Streptococcus pneumoniae isolates nonsusceptible to ceftriazone in children treated with beta-lactam antibiotics.

OBJECTIVE: To determine the outcome of children treated primarily with beta-lactam antibiotics for a systemic infection outside the central nervous system (CNS) caused by isolates of Streptococcus pneumoniae nonsusceptible to ceftriaxone (MIC > or = 1.0 microg/ml). DESIGN: Retrospective review of the medical records of children identified prospectively with invasive infections outside of the CNS caused by isolates of S. pneumoniae that were not susceptible to ceftriaxone between September, 1993, and August, 1999. A subset of this group treated primarily with beta-lactam antibiotics was analyzed for outcome. PATIENTS: Infants and children with pneumococcal infections cared for at eight children's hospitals. RESULTS: Among 2,100 patients with invasive infections outside the CNS caused by S. pneumoniae, 166 had isolates not susceptible to ceftriaxone. One hundred patients treated primarily with beta-lactam antibiotics were identified. From this group 71 and 14 children had bacteremia alone or with pneumonia, respectively, caused by strains with an MIC of 1.0 microg/ml. Bacteremia or pneumonia caused by isolates with a ceftriaxone MIC > or = 2.0 microg/ml occurred in 6 and 5 children, respectively. Three children with septic arthritis and 1 with cellulitis had infections caused by strains with an MIC to ceftriaxone of 1.0 microg/ml. Most were treated with parenteral ceftriaxone, cefotaxime or cefuroxime for one or more doses followed by an oral antibiotic. All but one child were successfully treated. The failure occurred in a child with severe combined immune deficiency and bacteremia (MIC = 1.0 microg/ml) who remained febrile after a single dose of ceftriaxone followed by 12 days of cefprozil. CONCLUSION: Ceftriaxone, cefotaxime or cefuroxime are adequate to treat invasive infections outside the CNS caused by pneumococcal isolates with MICs up to 2.0 microg/ml, a concentration currently considered resistant for these antibiotics by National Committee for Clinical Laboratory Standards breakpoints.

Linezolid for the treatment of community-acquired pneumonia in hospitalized children. Linezolid Pediatric Pneumonia Study Group.

OBJECTIVE: To determine the safety, tolerance, pharmacokinetics and efficacy of linezolid, a new oxazolidinone antibiotic in the treatment of community-acquired pneumonia in hospitalized children. DESIGN: A Phase II, open label multicenter study of intravenous linezolid followed by oral linezolid suspension, both at a dose of 10 mg/kg every 12 h. Efficacy was assessed at 7 to 14 days after the last dose of linezolid. PATIENTS: Children 12 months to 17 years old with community-acquired pneumonia admitted to the hospital of 14 participating centers. RESULTS: From July 21, 1998, through May 14, 1999, 79 children were enrolled and 78 received linezolid. Sixty-six children completed treatment and follow-up and were evaluable for clinical outcome. The median age of the evaluable patients was 3 years (range, 1 to 12 years); 47 were 2 to 6 years old. Pathogens were isolated from blood or pleural fluid cultures in 8 children: Streptococcus pneumoniae, 6 (2 penicillin-resistant); Group A Streptococcus, 1; methicillin-resistant Staphylococcus aureus, 1. Chest tubes were placed in 9 patients. The mean total duration of intravenous and oral administration was 12.2 +/- 6.2 days (range, 6 to 41 days). The mean peak and trough plasma concentrations of linezolid were 9.5 +/- 4.8 and 0.8 +/- 1.2 microg/ml, respectively. At the follow-up visit 7 to 14 days after the last dose of linezolid, 61 patients (92.4%) were considered cured including all the patients with proven pneumococcal pneumonia, one failed (methicillin-resistant Staphylococcus aureus) and 4 were considered indeterminate. The most common adverse effects in the intent to treat group were diarrhea (10.3%), neutropenia (6.4%) and elevation in alanine aminotransferase (6.4%). CONCLUSIONS: Linezolid was well-tolerated and could be considered an alternative to vancomycin for treating serious infections caused by antibiotic-resistant Gram-positive cocci in children pending results of additional studies.

Acute otitis media caused by Streptococcus pneumoniae in children's hospitals between 1994 and 1997.

OBJECTIVE: To determine patterns of resistance for isolates of Streptococcus pneumoniae recovered from middle ear fluids of children from eight children's hospitals between September, 1994, and August, 1997. METHODS: Data were extracted retrospectively from the medical records of eight children's hospitals. A standardized data form was completed for each episode of pneumococcal infection. Systemic isolates (blood and pleural, synovial and spinal fluids) of S. pneumoniae were collected during the same period. All isolates of S. pneumoniae from each center were sent to a central laboratory. Susceptibility to penicillin and ceftriaxone was determined by microbroth dilution. Organisms were considered nonsusceptible to penicillin if the minimum inhibitory concentration was > or = 0.1 microg/ml and nonsusceptible to ceftriaxone if the minimum inhibitory concentration was > or = 1.0 microg/ml. RESULTS: S. pneumoniae was recovered from the middle ear fluids of 707 children from all centers during the study period. Thirty-nine (5.5%) were infections recorded at 4 centers which evaluated middle ear fluid only sporadically and were not included in this analysis. The remaining 668 infections reported by the 4 remaining participating hospitals reflect the experience of 608 children. There were 54% boys; 440 (73%) were Caucasian, 111 (18%) were African-American, 38 (6%) were Hispanic and for 19 (3%) the race was not recorded. The children ranged in age from 16 days to 13.8 years with a mean (+/-sD) of 26.0 (+/- 26.1) months. Children who received antibiotics in the 30 days before the middle ear isolate was recovered were more likely to harbor a resistant strain of S. pneumoniae than children who had not recently received an antibiotic (P < 0.001). Isolates recovered from children with spontaneous otorrhea were more likely to be susceptible to penicillin than isolates recovered during myringotomy, with or without the insertion of tympanostomy tubes (P < 0.01). There was wide variation in the susceptibility of middle ear isolates to penicillin and ceftriaxone according to geographic location; however, in every locale the middle ear isolates were less likely to be susceptible to penicillin and ceftriaxone than systemic isolates of S. pneumoniae. CONCLUSION: The prevalence of penicillin-resistant and cephalosporin-resistant S. pneumoniae in middle ear isolates derived from children cared for at four different children's hospitals was quite variable. In some locations the prevalence of resistance is still increasing, whereas in other areas the rate of resistance was at a plateau during the period of surveillance. The prevalence of isolates of S. pneumoniae susceptible to penicillin and ceftriaxone was always less common among middle ear isolates than among systemic isolates. Previous antibiotic use remains the most predictive factor for the recovery of isolates resistant to penicillin and ceftriaxone.

Aseptic meningitis in a child after systemic treatment with high dose cytarabine.

Cytarabine was temporally associated with aseptic meningitis syndrome in an 8-year-old Hispanic girl being treated for acute lymphoblastic leukemia.

Nonrespiratory Stenotrophomonas maltophilia infection at a children's hospital.

To describe Stenotrophomonas maltophilia infection in children, we reviewed the medical records of patients with isolates from nonrespiratory sites and identified 85 episodes, 51 (60%) of which represented true infection. Forty-two episodes (82.4%) were hospital acquired. Commonly associated with S. maltophilia infection were underlying illness (in 90.2% of cases), previous hospitalizations (in 78.7%), previous antibiotic exposure (in 78.4%), and the presence of a central venous catheter (in 76.5%). Polymicrobial isolates were obtained in 70.6% of episodes; Pseudomonas aeruginosa and Acinetobacter species were the most common coisolates. Bloodstream infection was the most frequent clinical syndrome (32 [63%] of 51 episodes). Fever or sepsis occurred in 22 (69%) and shock in 10 (31%) of 32 episodes. Infection at other sites was less severe. The most active antibiotics in vitro were trimethoprim-sulfamethoxazole and ticarcillin-clavulanate. The overall and attributable mortality rates were 12.5% and 6.3%, respectively. S. maltophilia appears to be an important cause of nosocomially acquired bacteremia in children. The significance in children of isolation from other sites is less clear.

Pneumococcal facial cellulitis in children.

OBJECTIVE: To review the epidemiology and clinical course of facial cellulitis attributable to Streptococcus pneumoniae in children. DESIGN: Cases were reviewed retrospectively at 8 children's hospitals in the United States for the period of September 1993 through December 1998. RESULTS: We identified 52 cases of pneumococcal facial cellulitis (45 periorbital and 7 buccal). Ninety-two percent of patients were <36 months old. Most were previously healthy; among the 6 with underlying disease were the only 2 patients with bilateral facial cellulitis. Fever (temperature: >/=100.5 degrees F) and leukocytosis (white blood cell count: >15 000/mm(3)) were noted at presentation in 78% and 82%, respectively. Two of 15 patients who underwent lumbar puncture had cerebrospinal fluid with mild pleocytosis, which was culture-negative. All patients had blood cultures positive for S pneumoniae. Serotypes 14 and 6B accounted for 53% and 27% of isolates, respectively. Overall, 16% and 4% were nonsusceptible to penicillin and ceftriaxone, respectively. Such isolates did not seem to cause disease that was either more severe or more refractory to therapy than that attributable to penicillin-susceptible isolates. Overall, the patients did well; one third were treated as outpatients. CONCLUSIONS: Pneumococcal facial cellulitis occurs primarily in young children (<36 months of age) who are at risk for pneumococcal bacteremia. They present with fever and leukocytosis. Response to therapy is generally good in those with disease attributable to penicillin-susceptible or -nonsusceptible S pneumoniae. Ninety-six percent of the serotypes causing facial cellulitis in this series are included in the heptavalent-conjugated pneumococcal vaccine recently licensed in the United States.

Transactivation of latent Marek's disease herpesvirus genes in QT35, a quail fibroblast cell line, by herpesvirus of turkeys.

The QT35 cell line was established from a methylcholanthrene-induced tumor in Japanese quail (Coturnix coturnix japonica) (C. Moscovici, M. G. Moscovici, H. Jimenez, M. M. Lai, M. J. Hayman, and P. K. Vogt, Cell 11:95-103, 1977). Two independently maintained sublines of QT35 were found to be positive for Marek's disease virus (MDV)-like genes by Southern blotting and PCR assays. Sequence analysis of fragments of the ICP4, ICP22, ICP27, VP16, meq, pp14, pp38, open reading frame (ORF) L1, and glycoprotein B (gB) genes showed a strong homology with the corresponding fragments of MDV genes. Subsequently, a serotype 1 MDV-like herpesvirus, tentatively name QMDV, was rescued from QT35 cells in chicken kidney cell (CKC) cultures established from 6- to 9-day-old chicks inoculated at 8 days of embryonation with QT35 cells. Transmission electron microscopy failed to show herpesvirus particles in QT35 cells, but typical intranuclear herpesvirus particles were detected in CKCs. Reverse transcription-PCR analysis showed that the following QMDV transcripts were present in QT35 cells: sense and antisense meq, ORF L1, ICP4, and latency-associated transcripts, which are antisense to ICP4. A transcript of approximately 4.5 kb was detected by Northern blotting using total RNA from QT35 cells. Inoculation of QT35 cells with herpesvirus of turkeys (HVT)-infected chicken embryo fibroblasts (CEF) but not with uninfected CEF resulted in the activation of ICP22, ICP27, VP16, pp38, and gB. In addition, the level of ICP4 mRNA was increased compared to that in QT35 cells. The activation by HVT resulted in the production of pp38 protein. It was not possible to detect if the other activated genes were translated due to the lack of serotype 1-specific monoclonal antibodies.

Pneumococcal mastoiditis in children.

OBJECTIVE: To determine the impact of antibiotic resistance on the frequency, clinical features, and management/outcome of mastoiditis attributable to Streptococcus pneumoniae. DESIGN: Retrospective review of the medical records of children with mastoiditis caused by S pneumoniae from September 1993 through December 1998. PATIENTS: Infants and children with pneumococcal mastoiditis cared for at 8 children's hospitals in the United States. RESULTS: Thirty-four children with pneumococcal mastoiditis were identified. The median age of the children was 12 months (range: 2 months-12.5 years); 28 (82%) were

Clinical presentations, diagnosis, and prognostic factors of bacterial meningitis.

The clinical presentations of children and adults with bacterial meningitis have not changed over the past several decades, and a high index of suspicion remains critical for timely identification of infected patients. With the virtual disappearance of H. influenzae type B meningitis (Hib) in areas of the world where Hib conjugate vaccine is administered routinely, the utility of commercially available tests for rapid detection of bacterial polysaccharides has diminished. Detection of gene products of meningeal pathogens in cerebrospinal fluid or blood is still experimental. The prognostic findings of recent studies are not different from those previously described, despite advances in the supportive care of critically ill patients.

Congenital hypogonadotropic hypogonadism and micropenis: effect of testosterone treatment on adult penile size why sex reversal is not indicated.

Micropenis is commonly due to fetal testosterone deficiency. The clinical management of this form of micropenis has been contentious, with disagreement about the capacity of testosterone treatment to induce a functionally adequate adult penis. As a consequence, some clinicians recommend sex reversal of affected male infants. We studied 8 male subjects with micropenis secondary to congenital pituitary gonadotropin deficiency from infancy or childhood to maturity (ages 18 to 27 years). Four patients were treated with testosterone before 2 years of age (group I) and four between age 6 and 13 years (group II). At presentation, the mean penile length in group I was 1.1 cm (-4 SD; range, 0.5 to 1.5 cm) and in group II it was 2.7 cm (-3.4 SD; range, 1.5 to 3.5 cm). All patients received one or more courses of 3 intramuscular injections of testosterone enanthate (25 or 50 mg) at 4-week intervals in infancy or childhood. At the age of puberty the dose was gradually increased to 200 mg monthly and later to an adult replacement regimen. As adults, both group I and II had attained a mean final penile length of 10.3 cm 2.7 cm with a range of 8 to 14 cm (mean adult stretched penile length for Caucasians is 12.4 2.7 cm). Six of 8 men were sexually active, and all reported normal male gender identity and psychosocial behavior. We conclude that 1 or 2 short courses of testosterone therapy in infancy and childhood augment penile size into the normal range for age in boys with micropenis secondary to fetal testosterone deficiency; replacement therapy at the age of puberty results in an adult size penis within 2 SD of the mean. We found no clinical, psychologic, or physiologic indications to support conversion of affected male infants to girls. Further, the results of this study do not support the notion, derived from data in the rat, that testosterone treatment in infancy or childhood impairs penile growth in adolescence and compromises adult penile length.

Normal female infants born of mothers with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, especially those patients with the salt-losing form, have decreased fertility rates. Pregnancy experience in this population is limited. We report the pregnancy outcomes and serial measurements of maternal serum steroid levels in four women with classic 21-hydroxylase deficiency, three of whom were female pseudohermaphrodites with the salt-losing form. These glucocorticoid-treated women gave birth to four healthy female newborns with normal female external genitalia, none of whom were affected with 21-hydroxylase deficiency. In three women, circulating androgen levels increased during gestation, but remained within the normal range for pregnancy during glucocorticoid therapy. In the fourth patient, androgen levels were strikingly elevated during gestation despite increasing the dose of oral prednisone from 5 to 15 mg/day (two divided doses). Notwithstanding the high maternal serum concentration of androgens, however, placental aromatase activity was sufficient to prevent masculinization of the external genitalia of the female fetus and quite likely the fetal brain, consistent with the idea that placental aromatization of androgens to estrogens is the principal mechanism that protects the female fetus from the masculinizing effects of maternal hyperandrogenism. These four patients highlight key issues in the management of pregnancy in women with 21-hydroxylase deficiency, particularly the use of endocrine monitoring to assess adrenal androgen suppression in the mother, especially when the fetus is female. Recommendations for the management of pregnancy and delivery in these patients are discussed.

Acute N-methyl-D,L-aspartate administration stimulates the luteinizing hormone releasing hormone pulse generator in the ovine fetus.

To assess whether fetal luteinizing hormone releasing hormone (LH-RH) neurosecretory neurons have the capacity to respond to an exogenous stimulus, a synthetic excitatory amino acid analogue, N-methyl-D-L-aspartate (NMDA; 15 mg/kg), was given rapidly intravenously to 8 chronically catheterized fetuses (130-142 days of gestation; term 147 +/- 3 days). All 8 fetuses exhibited a rise in plasma ovine luteinizing hormone (oLH) and ovine follicle-stimulating hormone (oFSH) within 5 min. The mean maximal increments of oLH (2.25 +/- 0.36 ng/ml) and oFSH (1.21 +/- 0.32 ng/ml) were significantly greater than in 6 normal saline-injected controls (oLH p < 0.0002; oFSH p < 0.03). The secretion of ovine prolactin (oPRL) and ovine growth hormone (oGH) was unaffected. LH-RH (5 microg) evoked a greater oLH response (p < 0.0009) and a greater oFSH response (p < 0.03) than NMDA (n = 6). Desensitization of the fetal gonadotrope by a potent LH-RH agonist, D-Trp6Pro9NEt-LH-RH (10 microg/day i.v. x 4 days), abolished the fetal oLH and the oFSH response to NMDA (n = 5). Moreover, D, L-2-amino-5-phosphonovalerate, a specific competitive antagonist for the NMDA receptor, completely inhibited the fetal oLH and oFSH response to NMDA, whereas D-L-2-amino-5-phosphonovalerate alone did not affect the plasma oLH or oFSH levels, the gonadotropin response to LH-RH, or the release of oGH or oPRL (n = 3). In primary ovine fetal pituitary cell cultures, NMDA (10(-10) to 10(-6) M) had no effect on oLH, oFSH, oGH, or oPRL secretion, whereas LH-RH stimulated oLH (10(-8) M; p < 0.0004) and oFSH (10(-8) M; p < 0. 0001) release, evidence that NMDA did not have a direct pituitary effect. The results suggest that NMDA induces oLH and oFSH secretion by stimulation of the fetal LH-RH pulse generator and is mediated by central NMDA receptors. Fetal LH and FSH secretion and the response to LH-RH decrease in late gestation in the ovine and human fetus. The relative importance of sex steroid dependent and sex steroid independent central nervous system inhibition in this developmental change is unclear. It appears that central neural inhibition in addition to sex steroid negative feedback contributes to the decrease in fetal gonadotropin concentrations in late gestation. NMDA did not affect fetal oGH or oPRL secretion.