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Objective We describe five neonates with enteroviral (EV) infection to demonstrate central nervous system (CNS) and cardiac complications and report successful treatment of myocarditis with immunoglobulin intravenous (IVIG) in two. Study Design Case series identified during three enteroviral seasons in one neonatal intensive care unit (NICU) by cerebral spinal fluid (CSF) reverse transcriptase polymerase chain reaction (PCR) testing for EV in neonates suspected to have sepsis, but with sterile bacterial cultures. Results Cases were identified in each of three sequential years in a NICU with 800 to 900 admissions/year. Two cases were likely acquired perinatally; all were symptomatic with lethargy and poor feeding by age 5 to 10 days. All had signs of sepsis and/or meningitis; one progressed to periventricular leukomalacia and encephalomalacia. Two recovered from myocarditis after treatment that included IVIG 3 to 5 g/kg. Conclusion Neonates who appear septic without bacterial etiology may have EV CNS infections that can be diagnosed rapidly by CSF PCR testing. Cases may be underdiagnosed in the early neonatal period if specific testing is not performed. Neonates with EV infection should be investigated for evidence of periventricular leukomalacia, screened for myocarditis, and considered for IVIG treatment.

Objective The objective of this study was to estimate the annual rate of interhospital transfers of pregnant and postpartum women in the United States and analyze associated patient and health system characteristics as measures of regionalized perinatal care performance. Methods Separate weighted univariate analyses of the 2011 Nationwide Inpatient Sample (NIS) were performed for all maternal discharges, in-hospital deaths, and transfers. Multivariable logistic regression analyses for transfer dispositions adjusted for health system characteristics, maternal demographics, and diagnoses were performed. Additional perinatal service characteristics were analyzed using NIS merged with the 2011 American Hospital Association Annual Survey database. Results An estimated 18,082 patients, 0.43% of maternal hospitalizations, were transferred to an acute care hospital; 81% occurred without childbirth delivery before transfer. Transfers were toward larger, urban teaching hospitals and hospitals with higher levels of obstetrical and neonatal care and were more likely in states with ≥4.0 maternal–fetal medicine specialists/10,000 live births. Blacks and Native Americans were more likely and Hispanics and Asians were less likely than white patients to be transferred. Privately insured women were less likely to be transferred than were others. Transfers were associated with life-threatening maternal diagnoses and fetal indications. Conclusion Transfers reflected a risk-based regionalized system of perinatal care, with racial and payer differences.

The high neonatal mortality rate in the United States relative to other developed countries is a national concern (Healthy People 2020 2010; World Health Organization 2010). The major clinical conditions associated with death in early infancy include premature birth; congenital malformation; sepsis; respiratory distress syndrome (RDS); necrotizing enterocolitis (NEC); hypoxia; intraventricular hemorrhage (IVH); and maternal conditions and complications involving the placenta, umbilical cord, and/or delivery (Guthrie et al. 2003; Shankaran et al. 2005; Heron et al. 2009). A system of regionalized perinatal care has evolved to deliver specialized care to high-risk obstetrical and neonatal patients (American Academy of Pediatrics Committee on the Fetus and Newborn 2012). However, in a voluntary system of regionalized perinatal care in which some patients are uninsured, health insurance status may affect access to neonatal intensive care and the neonatal mortality rate. Being uninsured is harmful to the health of older children and adults, and their health status may be improved by acquisition of insurance and access to health care services (Institute of Medicine 2009). The aims of this analysis are to use a national hospital discharge survey database to estimate the contribution of insurance status to access to health care resources and to neonatal survival outcome, adjusted for the diagnoses and demographic characteristics that are associated with neonatal death.

Objective To identify characteristics predictive of survival of patients with congenital diaphragmatic hernia (CDH). Study Design Retrospective analysis of clinical characteristics including severity of lung disease measured by oxygenation index (OI) associated with single-center survival in CDH patients (n = 81) from 1992 to 2008. Data were analyzed using univariate and multivariable logistic regression, effect plots, and receiver operating characteristic (ROC) plots. Results No patient died if the stomach was located in the abdomen. A left thoracic stomach position predicted decreased survival with ROC area under the curve (AUC) = 0.70. OI of ≤26 averaged over the first 12 hours of life predicted ≥50% survival for all patients, with AUC = 0.86. OI effect plots allow prediction of survival over a continuous OI range. No patient survived if mean OI was >51 in the first 12 hours of life. Delaying surgery for a median of 6 days improved survival probability for all patients with presurgery OI values ≤51. Conclusion Position of the stomach in the abdomen, delayed surgery, and less severe cardiopulmonary disease during the first 12 hours of life, as measured by mean OI, predicted improved survival probability among patients with CDH. Our CDH model, using mean OI, permits specific individual prediction of survival probability over a range of OI values.

ObjectiveTo determine the effect of intention to breast-feed on short-term breast-feeding outcomes in women delivering term and preterm infants.DesignData from the US Centers for Disease Control and Prevention's Pregnancy Risk Assessment Monitoring System (PRAMS) for three states, Ohio, Michigan and Arkansas, during 2000–2003 were analysed. SAS 9·1·3 and SUDAAN 10 statistical software packages were used for analyses.SettingArkansas, Michigan and Ohio, USA.SubjectsMothers of recently delivered infants, selected by birth certificate sampling.ResultsOf 16 839 mothers included, 9·7 % delivered preterm. Some 52·2 % expressed definite intention to breast-feed, 16·8 % expressed tentative intention, 4·3 % were uncertain and 26·8 % had no intention to breast-feed. Overall 65·2 % initiated breast-feeding, 52·0 % breast-fed for ≥4 weeks and 30·8 % breast-fed for ≥10 weeks. Women with definite intention were more likely to initiate (OR = 24·3, 95 % CI 18·4, 32·1), to breast-feed for ≥4 weeks (OR = 7·12, 95 % CI 5·95, 8·51) and to breast-feed for ≥10 weeks (OR = 2·75, 95 % CI 2·20, 3·45) compared with women with tentative intention. Levels of intention did not differ between women delivering preterm and term. Women delivering at ConclusionsPrenatal intention to breast-feed is a powerful predictor of short-term breast-feeding outcomes in women delivering both at term and prematurely.

Purpose The risk of adverse drug events (ADEs) in neonates treated with opioids and the effect of a bar-code-assisted medication administration (BCMA) system were studied. Methods A prospective cohort study of neonates in a neonatal intensive care unit (NICU) was conducted. A BCMA system was operative for 50% of the study period. Structured medical record audits were conducted to identify medication errors and preventable ADEs. Stratified frequency distribution and Cox proportional hazards analyses were used. Results Of 618 patients, 78 (12.6%) received postoperative care, 280 (45.3%) required assisted ventilation, and 72 (11.7%) were treated with opioids during their hospitalization. A total of 32 first preventable ADEs occurred. Univariate analyses demonstrated that postoperative status, assisted ventilation, and opioid administration were each significantly associated with ADEs. However, stratified frequency distribution analyses indicated that opioid administration during hospitalization was associated with preventable ADEs, controlling for postoperative status ( p = 0.0019) or assisted ventilation ( p = 0.0007). The odds ratio for any preventable ADE occurrence in a patient treated with an opioid was 4.74 compared with an infant not treated with an opioid. Patients who were treated with an opioid in the absence of a BCMA system had a 10% probability of an ADE after hospitalization for six days. Conclusion Infants in a NICU who were treated with opioids were at greater risk of a preventable ADE than other patients, adjusted for two medical conditions, assisted ventilation and postoperative status. A BCMA system reduced the risk of harm from an opioid medication error.

Adverse medical events and adverse drug events are not uncommon in NICUs, and research has been directed at determining the causes of such events as well as potential methods of reducing their occurrence. Both human fallibility and the complex adaptive system that comprises the NICU present opportunities for errors. Human factors engineering and systems can improve reliability, as can computer systems for ordering, dispensing, administering, and monitoring drugs. Barcode scanning medication dispensing and administration systems and smart pumps also have been investigated. Human factors that have contributed to errors include fatigue, communication failure, poor handoffs, problems with cross-coverage, workload, and staffing patterns. Addressing these factors can aid in reducing medical errors.

Background Red blood cell (RBC) transfusions in very low birthweight (VLBW) infants, while common, carry risk. Our objective was to determine clinical predictors of and trends in RBC transfusions among VLBW infants. Methods RBC transfusion practice and its clinical predictors in 1,750 VLBW (≤1500 g) infants were analyzed in a single-center cohort across sequential epochs: 2000–2004 (Epoch 1), 2005– 2009 (Epoch 2), and 2010–2013 (Epoch 3). Results Overall, 1,168 (67 %) infants received ≥1 transfusions. The adjusted likelihood of ≥1 transfusions decreased for each 1-g/dL increment in initial hemoglobin concentration following birth, for females, and for each 100-g increment in birthweight. The adjusted likelihood of ≥1 transfusions increased with infants receiving mechanical ventilation, with increasing length of hospital stay, with necrotizing enterocolitis and with non-lethal congenital anomalies requiring surgery. The adjusted mean (SEM) number of transfusions per patient was decreased in Epoch 3, compared with Epoch 1 and Epoch 2. For an initial hemoglobin of ≥16.5 g/dL, the predicted probability of being transfused was ≤50%. Conclusion Adjusted RBC transfusions declined and female sex conferred an unexplained protection over the study period. Modest increases in initial hemoglobin by placentofetal transfusion at delivery may reduce the need for RBC transfusion.

Importance Reduced death and neurodevelopmental impairment among infants is a goal of perinatal medicine. Objective To assess the association between surgery during the initial hospitalization and death or neurodevelopmental impairment of very low-birth-weight infants. Design, Setting, and Participants A retrospective cohort analysis was conducted of patients enrolled in the National Institute of Child Health and Human Development Neonatal Research Network Generic Database from 1998 through 2009 and evaluated at 18 to 22 months’ corrected age. Twenty-two academic neonatal intensive care units participated. Inclusion criteria were birth weight 401 to 1500 g, survival to 12 hours, and availability for follow-up. A total of 12 111 infants were included in analyses. Exposures Surgical procedures; surgery also was classified by expected anesthesia type as major (general anesthesia) or minor (nongeneral anesthesia). Main Outcomes and Measures Multivariable logistic regression analyses planned a priori were performed for the primary outcome of death or neurodevelopmental impairment and for the secondary outcome of neurodevelopmental impairment among survivors. Multivariable linear regression analyses were performed as planned for the adjusted mean scores of the Mental Developmental Index and Psychomotor Developmental Index of the Bayley Scales of Infant Development, Second Edition, for patients born before 2006. Results A total of 2186 infants underwent major surgery, 784 had minor surgery, and 9141 infants did not undergo surgery. The risk-adjusted odds ratio of death or neurodevelopmental impairment for all surgery patients compared with those who had no surgery was 1.29 (95% CI, 1.08-1.55). For patients who had major surgery compared with those who had no surgery, the risk-adjusted odds ratio of death or neurodevelopmental impairment was 1.52 (95% CI, 1.24-1.87). Patients classified as having minor surgery had no increased adjusted risk. Among survivors who had major surgery compared with those who had no surgery, the adjusted risk of neurodevelopmental impairment was greater and the adjusted mean Bayley scores were lower. Conclusions and Relevance Major surgery in very low-birth-weight infants is independently associated with a greater than 50% increased risk of death or neurodevelopmental impairment and of neurodevelopmental impairment at 18 to 22 months’ corrected age. The role of general anesthesia is implicated but remains unproven.

To investigate whether observed vs expected (O/E) lung–to–head ratio (LHR) correlates with neonatal survival in infants with congenital diaphragmatic hernia (CDH). Secondary goal was to correlate O/E LHR with Oxygenation index (OI) in the first 12 hours of life.

Background To determine the effect of human milk, maternal and donor, on in-hospital growth of very low birthweight (VLBW) infants. We performed a retrospective cohort study comparing in-hospital growth in VLBW infants by proportion of human milk diet, including subgroup analysis by maternal or donor milk type. Primary outcome was change in weight z-score from birth to hospital discharge. Methods Retrospective cohort study. Results 171 infants with median gestational age 27 weeks (IQR 25.4, 28.9) and median birthweight 899 g (IQR 724, 1064) were included. 97% of infants received human milk, 51% received > 75% of all enteral intake as human milk. 16% of infants were small-for-gestational age (SGA, < 10th percentile) at birth, and 34% of infants were SGA at discharge. Infants fed >75% human milk had a greater negative change in weight z-score from birth to discharge compared to infants receiving < 75% (−0.6 vs, -0.4, p = 0.03). Protein and caloric supplementation beyond standard human milk fortifier was related to human milk intake (p = 0.04). Among infants receiving > 75% human milk, there was no significant difference in change in weight z-score by milk type (donor −0.84, maternal −0.56, mixed −0.45, p = 0.54). Infants receiving >75% donor milk had higher rates of SGA status at discharge than those fed maternal or mixed milk (56% vs. 35% (maternal), 21% (mixed), p = 0.08). Conclusions VLBW infants can grow appropriately when fed predominantly fortified human milk. However, VLBW infants fed >75% human milk are at greater risk of poor growth than those fed less human milk. This risk may be highest in those fed predominantly donor human milk.

OBJECTIVE: The goal was to examine the impact of birth at night, on the weekend, and during July or August (the first months of the academic year) and the impact of resident duty-hour restrictions on mortality and morbidity rates for very low birth weight infants. METHODS: Outcomes were analyzed for 11 137 infants with birth weights of 501 to 1250 g who were enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network registry in 2001–2005. Approximately one-half were born before the introduction of resident duty-hour restrictions in 2003. Follow-up assessments at 18 to 22 months were completed for 4508 infants. Mortality rate, short-term morbidities, and neurodevelopmental outcome were examined with respect to the timing of birth. RESULTS: There was no effect of the timing of birth on mortality rate and no impact on the risks of short-term morbidities except that the risk of retinopathy of prematurity (stage ≥2) was higher after the introduction of duty-hour restrictions and the risk of retinopathy of prematurity requiring operative treatment was lower for infants born during the late night than during the day. There was no impact of the timing of birth on neurodevelopmental outcome except that the risk of hearing impairment or death was slightly lower among infants born in July or August. CONCLUSION: In this network, the timing of birth had little effect on the risks of death and morbidity for very low birth weight infants, which suggests that staffing patterns were adequate to provide consistent care.

To determine genetic and clinical risk factors associated with elevated systolic blood pressure (ESBP) in preterm infants after discharge from the neonatal intensive care unit (NICU).A convenience cohort of infants born at32 weeks gestational age was followed after NICU discharge. We retrospectively identified a subgroup of subjects with ESBP (systolic blood pressure [SBP]90th percentile for term infants). Genetic testing identified alleles associated with ESBP. Multivariate logistic regression analysis was performed for the outcome ESBP, with clinical characteristics and genotype as independent variables.Predictors of ESBP were cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6) (rs28360521) CC genotype (OR, 2.92; 95% CI, 1.48-5.79), adjusted for outpatient oxygen therapy (OR, 4.53; 95% CI, 2.23-8.81) and history of urinary tract infection (OR, 4.68; 95% CI, 1.47-14.86). Maximum SBP was modeled by multivariate linear regression analysis: maximum SBP=84.8 mm Hg + 6.8 mm Hg if cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6) CC genotype + 6.8 mm Hg if discharged on supplemental oxygen + 4.4 mm Hg if received inpatient glucocorticoids (P=.0002).ESBP is common in preterm infants with residual lung disease after discharge from the NICU. This study defines clinical factors associated with ESBP, identifies a candidate gene for further testing, and supports the recommendation to monitor blood pressure before age 3 years, as is suggested for term infants.

A bar code medication administration (BCMA) system reduced preventable adverse drug events (ADEs) by 47% in our neonatal intensive care unit (NICU). However, it is often expected that providers will not welcome technological change. Two years after BCMA system implementation, we studied the perceptions of nurses in our NICU to better understand their opinions about patient safety, use, acceptance and occupational effects of the new technology. Forty-six nurses (median age < 30 years) completed a 30-item questionnaire. Most nurses reported comfort using the system within two weeks. The majority believed that the system had prevented a medication error or ADE, although they were aware that medication errors persisted and workarounds occurred. Most reported that medication administration required more time with the BCMA system, but they believed that the alerts, which most reported occurred with < or =25% scheduled administrations, were not excessive. Over half of the nurses felt that the new system improved job satisfaction and increased professionalism. Although overall stress levels were moderate, nurses reported greater stress resulting from computer breakdowns than from other situations. Nurses reported strong support from supervisors, physicians and hospital administrators. These nurses were adaptive to the new technology when they believed it increases patient safety, nursing professionalism and job satisfaction and when they were supported by colleagues.

To conduct a systematic review and meta-analyses of studies that test the association between induced or spontaneous abortion and subsequent preterm birth.International databases were reviewed (1995-2007) using the terms preterm, premature, birth, labor, delivery, abortion, induced abortion, miscarriage and spontaneous abortion. Only studies that met prespecified objective criteria for methodologic design and reporting were included in the meta-analyses.Twelve induced and 9 spontaneous abortion studies met inclusion criteria. Common adjusted odds ratios (ORs) for preterm birth following 1 andor = 2 induced abortions were 1.25 (95% confidence interval [95% CI] 1.03-1.48) and 1.51 (95% CI 1.21-1.75), respectively. Four studies provided a common adjusted OR foror = 32 weeks' births of 1.64 (95% CI 1.38-1.91). Meta-regression analysis revealed a previously unrecognized inverse relationship between the In OR and the control population preterm birth rate, explaining in part the observed heterogeneity among studies. Analysis of spontaneous abortion and subsequent preterm birth revealed a similar common adjusted OR and inverse meta-regression on the control preterm birth rates.Induced and spontaneous abortion are associated with similarly increased ORs for preterm birth in subsequent pregnancies, and they vary inversely with the baseline preterm birth rate, explaining some of the variability among studies.

OBJECTIVE: To estimate observed compared with predicted survival rates of extremely premature infants born during 2000–2009, to identify contemporary predictors of survival, and to determine if improved survival rates occurred during the decade. METHODS: We conducted a retrospective cohort analysis of 237 inborn neonates without major congenital anomalies born from 2000 to 2009 after 22 to 25 completed weeks of gestation. Observed survival rates at each gestational age were compared with predicted survival rates based on gestational age, birth weight, sex, singleton or multiple gestation, and antenatal corticosteroid administration estimated by a Web-based calculator that was derived from 1998 to 2003 outcomes of a large national cohort. Multivariable logistic regression analysis was used to identify significant predictors of survival of the study cohort, including year of birth. RESULTS: Survival rates for the decade by gestational age (compared with predicted rates) were: 22 weeks, 33% (compared with 19%); 23 weeks, 58% (compared with 38%); 24 weeks, 87% (compared with 58%); and 25 weeks, 85% (compared with 70%). Antenatal corticosteroids were administered in 96% of pregnancies. Variables that significantly predicted survival and their odds ratios (OR) with 95% confidence intervals (CI) are: antenatal corticosteroid administration (OR 5.27, CI 1.26–22.08); female sex (OR 3.21, CI 1.42–7.26); gestational age (OR 1.89, CI 1.27–2.81); 1-minute Apgar score (OR 1.39, CI 1.15–1.69); and birth year (OR 1.17, CI 1.02–1.34). The number needed to treat with any antenatal corticosteroid therapy to prevent one death was 2.4. CONCLUSION: In this single-institution cohort treated aggressively (antenatal corticosteroid administration [even if less than 24 weeks], tocolysis until steroid course complete, cesarean for fetal distress) by perinatologists and neonatologists, survival rates at 22–25 weeks of gestation age for inborn infants during the 2000s exceeded predicted rates, with increasing odds of survival during the decade. Antenatal corticosteroid administration had a significant effect on survival. (Obstet Gynecol 2012;119:795–800)

Patients are at risk of harm from medication errors. Barcode medication administration (BCMA) systems are recommended to mitigate preventable adverse drug events (ADEs). Our hypothesis was that a BCMA system would reduce preventable ADEs by 45% in a neonatal intensive care unit.We conducted a prospective, observational, cohort study of a BCMA system intervention in a neonatal intensive care unit. Participants were admitted neonates during 50 weeks. Medication errors and potential or preventable ADEs were detected by a daily structured audit of each subject's medical record, with assignment of an event as a preventable ADE made by blinded assessors. The generalized estimating equation method was used in modeling the targeted, preventable ADE rate with covariates.A total of 92,398 medication doses were administered to 958 subjects. The generalized estimating equation method yielded a relative risk of preventable ADE when the system was implemented of 0.53 (95% confidence limits 0.29 to 0.91, P = .04), adjusted for log(10)doses of medication/subject/day, a significant predictive covariate (P.001), as well as for birth weight, sex, Caucasian race, birth cohort number, and nursing hours/subject/day.The BCMA system reduced the risk of targeted, preventable ADEs by 47%, controlling for the number of medication doses/subject/day, an important risk exposure.

We investigated the presence of volatile aliphatic amines by fluorescamine and gas chromatographic-head space analysis in human breast milk and amniotic fluid to assess their role in neonatal hypergastrinemia. These volatile nitrogenous amino acid metabolites have been previously demonstrated to stimulate gastrin release in in vivo and in vitro laboratory preparations. In the present study we demonstrated that these gastrin-stimulatory volatile amines were present in significant concentrations in breast milk during the first several weeks after parturition and in amniotic fluid. The individual amines that were identified in both human milk and amniotic fluid samples were methylamine, dimethylamine, ethylamine, trimethylamine, propylamine, isobutylamine, and butylamine. This study provides indirect evidence to support the possibility that the hypergastrinemia measured in the fetus/neonate during the period immediately before and after birth may be attributable, in part, to the ingestion of fluid containing high concentrations of gastrin-stimulating amines.

Frank H. Morriss, Jr., MD, Mary lynn Moore , RN, Tina Gibson, BSN, a n d M. S tewa r t West, PhD From the Department of Pediatrics, University of Iowa College O f Medicine, Iowa City, the Department of Pediatrics, Medical School of the University of Texas Health Science Center at Houston, the Department of Internal Medicine, Baylor College of Medicine, Houston, and the University Children's Hospital at Hermann, Houston, Texas

Human milk pH was measured in 309 samples obtained from 52 women who had delivered at term and lactated for as long as 10 months thereafter. The mean pH decreased from 7.45 for colostrum to a nadir of 7.04 during the second week of lactation. Thereafter, the pH of milk remained between 7.0 and 7.1 until 3 months postpartum and then increased gradually to 7.4 by 10 months. The change in hydrogen ion concentration in milk was associated with corresponding changes throughout lactation in the concentration of citrate but not with the concentration of lactose. Lactose concentration increased gradually for 3 weeks; the concentration of saturated medium-chain fatty acids increased more rapidly. One interpretation of these findings is that the hydrogen ions and citrate generated by mammary secretory cell metabolism are used after the second week of lactation for de novo synthesis of fatty acids more rapidly than they are synthesized. Milk samples from ruminants were found to have concentrations of hydrogen ions and citrate that are greater than and pH that is less than the respective measurements in human milk. The significance for the recipient infant of the predictable changes in human milk pH during lactation and of the higher pH of human milk throughout lactation relative to bovine milk is unknown. However, drug excretion into milk, milk enzyme activity, milk leukocyte function, and neonatal gastroin-testinal function are affected by ambient pH and may be influenced by the pH of milk.

Nine episodes of the syndrome of inappropriate antidiuretic hormone secretion occurred in five newborn infants following atelectasis or pneumothorax. All infants had pre-existing lung disease and were being treated with positive pressure ventilation. The mean interval between acute atelectasis or pneumothorax and the development of diagnostic hyponatremia, hypo-osmolal serum, hyperosmolal urine, and oliguria was 13.4 hours. Fluid restriction and removal of the triggering event resulted in resolution of the abnormalities within 1.5 to 4 days. Infants who develop atelectasis or pneumothorax should be evaluated for the subsequent occurrence of SIADH; the administration of a water load to them may result in dilutional hyponatremia, for which fluid restriction, not sodium infusion, is the proper therapy.

Summary: Although glucose is an important fuel for fetal oxidative metabolism, regulation of its availability to the mammalian fetus is poorly understood. This study was performed to determine the effect of infusions of insulin into the uterine arterial circulation on umbilical uptake of glucose in chronically instrumented, unstressed sheep. Twenty-eight determinations of umbilical glucose uptake and diffusion clearance of glucose by the placenta were made in four ewes. Immediately following a control study during which saline was infused into the uterine artery, porcine regular insulin diluted in saline was infused at 0.05 to 8.1 mU/min · kg uterine weight for 20–30 min and the determinations were repeated. Subsequent studies were performed at the conclusion of additional infusions of insulin to a maximum of 21.6 mU/min · kg. There was a significant increase in umbilical glucose uptake during initial insulin infusions (4.47 ± 0.6 mg/min · kg fetus) compared to the control studies (3.08 ± 0.6 mg/min · kg) associated with an increase in diffusion clearance (13.8 ± 1.9 ml/min · kg fetus vs. 8.99 ±1.8 ml/min · kg). When the total cumulative dose of exogenous insulin, It, was 162 mU/kg uterine weight or less, the umbilical uptake of glucose, Q, may be expressed as a function of maternal arterial blood glucose concentration in milligrams per dl, [A], and of It. Speculation: Exogenous insulin infused at physiologic rates into the ovine uterine artery increases the permeability of the placenta to glucose by increasing the initial rate of glucose transport by a carrier system into cells which comprise the placenta until insulin receptor sites are saturated.

The movement of newborn infants from the delivery room of a level III perinatal center to nursing units that provided different levels of care was prospectively documented for 1975 and 1976. These data were employed in a computer modeling experiment based on sequential queuing theory to determine the relationships between numbers of available intermediate and maximum care nursery beds, the probability that a given newborn arrival could not be accommodated, and the occupancy rates for each level of care. The nursery bed requirements for the level III center were used to estimate the number of special care beds needed by the regional Health Service Area.

The growth of uterine oxygen and glucose uptakes (Qo2, Q glucose) throughout pregnancy was determined in sheep with chronically implanted uterine artery electromagnetic flow probes and arterial and uterine venous catheters. The flow probe measurements were corrected to total uterine blood flow by means of an equation based on simultaneous flow probe and radioactive microsphere determinations. Uterine Qo2, and Q glucose increased logarithmically as gestation progressed. During the last third of gestation, the mean Qo2 for twin pregnancies was 44% higher than Qo2 for single pregnancies. In the last 3 weeks of gestation the uterine glucose/oxygen quotient was 0.76 (95% confidence limits 0.65–0.87), which is significantly less than one and significantly greater than the 0.46 umbilical glucose/oxygen quotient determined in previous studies. This result indicates that substrates other than glucose are used in large amounts in order to satisfy the requirements of uterine oxidative metabolism in late pregnancy and that the placenta has a relatively high glucose/oxygen quotient. Uterine arteriovenous differences of fructose and pyruvate measured at intervals throughout gestation revealed that there is no significant uptake of these substrates by the pregnant uterus.

In 18 chronically instrumented pregnant ewes in late gestation, umbilical extractions of glucose and lactate were determined before and during the continuous infusion of ovine insulin, 0.25 mU/kg . min, into one uterine artery. Studies were conducted in both well-nourished and fasting ewes. Exogenous insulin increased the umbilical extraction of glucose without altering the umbilical extraction of lactate over the range of concentrations of maternal blood glucose encountered in the fed and fasted states. Moreover, the efflux of lactate into the uterine venous circulation in two additional ewes was not altered by the administration of insulin. These studies support the hypothesis that maternal circulating insulin binds to insulin receptors on the microvillous brush border of the placenta to effect an increase in the carrier-mediated transfer of glucose rather than cause an intraplacental decrease in the catabolism of glucose to lactate. The results suggest that, as maternal levels of blood glucose and serum insulin spontaneously rise in concert over the physiologic range, both factors may contribute to the increasing umbilical extraction of glucose. Furthermore, these observations raise the possibility that decreased binding of insulin by placental insulin receptors, which is reported to occur in placentas from diabetic women, may be accompanied by a relatively decreased umbilical uptake of glucose for a given maternal concentration of glucose, but not of lactate.

The activity of UDP-D-xylose: proteoglycan core protein β-D-xylosyltransferase (EC 2.4.2.26), the enzyme that catalyzes the initiation of the polysaccharide chain linkage to the core protein of proteoglycans, was measured in costal cartilage from 20 fetal sheep of 65-138 days gestation. Activity of the enzyme was estimated from the transfer of [14C]xylose from UDP-[14C]xylose to silk as the acceptor protein. The specific activity decreased approximately 10-fold and was found to be highly correlated with the decremental rate of growth in length of the fetal vertebral column. These observations, together with the known gestational decrease in the in vitro rate of uptake of radio labeled sulfate by ovine fetal cartilage, a subsequent step in proteoglycan synthesis, support the hypothesis that normal fetal skeletal growth is dependent during the last one-half of gestation on the activity of xylosyltransferase in cartilage.

Duodenal motility was studied by intraluminal manometry in 27 healthy infants of 26 to 42 weeks, gestational age. The frequency of contractions, the number of contractions per burst, and the intraluminal peak pressure during contractions all increased during a narrow postconceptual period, 29 to 32 weeks, regardless of length of gestation before birth. Antenatal β-methasone administration to the mothers of 11 additional infants of 26 to 32 weeks gestational age was associated with creased duodenal contraction rate, number of contracintions per burst, and intraluminal peak pressure compared with infants of similar gestational age whose mothers did not receive β-methasone. The maturational effect of β-methasone on duodenal motility was most pronounced in infants whose gestational age at birth was 26 to 29 weeks. Seven infants of 31 weeks' or longer gestational duration who had a CNS abnormality or insult had fasting duodenal contraction rates that were less than one half of the rate for normal infants of similar gestational age. These observations suggest that neonatal duodenal motility undergoes marked maturational changes between 29 and 32 weeks after conception and that these changes may be inducible before 29 weeks by corticosteroid administration. An intact CNS appears to be required for full expression of the maturational changes.

Infusion of gastrin, G-17I, at 0.4 microgram/min into either the maternal or fetal venous circulation of six late gestation sheep was associated with increases in serum gastrin concentration in the infused circulation and reciprocal decreases in the serum gastrin concentration in the other circulation (contraplacental) that perfused the placenta. Pentagastrin infusion at 0.4 microgram/min was associated with an increase in C-terminal specific gastrin immunoreactivity in both the infused and the contraplacental circulations. These observations suggest that biologically active fragments of gastrin, but not the intact molecule, may cross the ovine placenta. An alternative explanation for our results is that gastrin infusion into either the maternal or fetal circulation which perfuses the placenta may result in the release of an inhibitor (i.e., somatostatin) into the other circulation. Of broad importance, these observations indicate that although intact polypeptide hormones may not traverse the placenta, their concentrations in maternal and fetal sera may not be as independent as previously believed. Serum gastrin half-life values in late gestation sheep fetuses, lambs, and ewes were determined to be 13.7 +/- 1.9, 16.7 +/- 2.6, and 15.2 +/- 2.8 min, respectively. These similar values indicate that the relatively high serum gastrin concentrations observed in near-term sheep fetuses are not the result of prolonged half-life in the fetus.

PHAGOCVTOSIS and killing of bacteria by human polymorphonuclear leukocytes is accompanied by a number of oxidative alterations, including increases in hexose monophosphate shunt activity, oxygen consumption, and hydrogen peroxide production. I The purposes of this study were (1) to investigate H MPS activity in resting and phagocytizing PMNL obtained from infected and healthy infants, (2) to determine the bactericidal activity of PMNL obtained from healthy control infants and adults in the presence of either adult or infant serum, using Staphylococcus aureus and Escherichia coli as the test organisms, and (3) to compare bactericidal activity with HMPS activity in healthy control infants and adults.

The intraerythrocytic 2,3-diphosphoglycerate concentration in cord blood from 7 meconium-stained newborn infants was 2.91 ± 0.32 μM per milliliter as compared to control values of 4.39 ± 0.22. The mean hematocrit for the meconium-stained group was higher than that for the control group. No pH, birth weight, or gestational age difference was observed between the 2 groups. The relationship to intrauterine hypoxia is discussed.

Summary: Human and ovine placental tissue homogenates were assayed for dipeptidase activity in vitro. Glycyl-L-leucine, L-leucyl glycine, glycyl-L-lysine, and L-lysyl glycine were hydrolyzed by placental homogenates. The pH optimum for the reaction was 8.0. The relationship between enzyme activity and concentration was linear for placental homogenate concentrations between 0.01 and 0.10 mg protein/ml of reaction mixture. Enzyme activities were 1.92 ± 0.12 (S.E.) μoles/min/mg protein for hydrolysis of glycyl-L-leucine, 0.34 ± 0.06 (S.E.) μmoles/min/mg protein, for hydrolysis of glycy-L-lysine by human placenta, and 2.79 ± 0.8U μmoles/min/mg protein and 0.41 ± 0.25 μmoles/min/mg protein, respectively, by ovine placenta. The infusion of glycyl-L-lucine into the uterine artery of unstressed catheterized pregnant ewes yielded increased concentrations of both component amino acids in uterine venous blood and of leucine in umbilical venous blood. Speculation: The presence of dipeptidase activity in placental homogenates and the observation that glycyl-L-leucine when infused into the main uterine artery is hydrolyzed to its component amino acids support the hypothesis that leucine and possibly glycine extracted from the placenta by the umbilical circulation may be provided by placental hydrolysis of dipeptides which arise within the placenta from the degradation of larger peptides and proteins.

The blood flows to reproductive organs were measured by means of radionuclide-labeled microspheres in 24 pregnant ewes with gestational ages ranging from 38 to 141 days. The microspheres were injected in the left ventricle of the non-anesthetized animal 4–7 days after surgery and while uterine blood flow was recorded continously by means of electromagnetic probes on both uterine arteries. The blood flow to ovaries with corpus luteum was maximum in early pregnancy and greater than in ovaries without corpus luteum. Placental blood flow increased from ∼30 to ∼300 ml/min during the stage of placental growth (40–90 days). In the last 50 days of pregnancy placental weight declined, whereas placental flow continued to rise and attained ∼1,500 ml/min near term. The growth curves of fetal weight and placental blood flow followed a similar pattern, but the early increase in placental flow was more rapid than the increase in fetal weight. Hence placental flow per gram of fetus was larger in early pregnancy (∼9 ml/min·g) than near term (∼0.25 ml/min·g). In twin pregnancies the placenta of each fetus received a smaller blood flow than the placenta of a singleton of comparable age. Mammary blood flow demonstrated no change until the last 60 days, when it increased from ∼10 to ∼200 ml/min. This phenomenon coincided with an increase in mammary weight and the final progressive increase of placental blood flow.

• Four term infants were found by computerized cerebral tomography (CT) to have intraventricular hemorrhage. All were male infants who had experienced substantial intrapartum complications. One infant had subtle clinical signs at 2 days of age; the others had major neurologic findings including seizures and ophthalmoplegia that occurred at 1,4, and 6 weeks of age, respectively. Three infants in whom the hemorrhages were indistinguishable by CT from those described in preterm infants now have arrested hydrocephalus and normal development. The fourth infant was found to have a large glioblastoma at the site of origin of his initial hemorrhage. These cases emphasize the need to consider this diagnosis in neonates born at term who have abnormal neurologic signs. ( Am J Dis Child 133:941-944, 1979)

Conclusions(a) Starvation in the pregnant ewe is associated with an increase in maternal blood concentrations of acetoacetate and β-hydroxybutyrate.(b) Despite elevated maternal concentrations of acetoacetate, the umbilical venous-arterial blood acetoacetate difference does not change during maternal starvation. However, rising maternal levels of β-hydroxybutyrate are associated with increasing umbilical venous-arterial β-hydroxybutyrate concentration differences.(c) Neither acetoacetate nor β-hydroxybutyrate umbilical uptake is used by the sheep fetus as a major fuel of aerobic metabolism, even during maternal starvation.

In vitro assays for [35S]sulfate uptake by ovine fetal costal cartilage were used to assess gestational changes in cartilage metabolism. Addition of 20% normal human serum to the incubation medium increased fetal cartilage [35S]sulfate incorporation into glycosaminoglycans. Both basal and human serum-stimulated uptakes of [35S]sulfate by fetal sheep cartilage decreased from midgestation to full term. The incremental response in [35S]sulfate uptake that was stimulated by human serum decreased as gestation proceeded to full-term. Fetal serum sulfate concentration decreased logarithmically during gestation, raising the possibility that cartilage sulfate uptake might become substrate limited as full term is approached. Perfusion of seven late gestation sheep fetuses for 7 days with Na2SO4 to achieve serum sulfate concentrations similar to those observed earlier in gestation resulted in a 33% increase in mean cartilage [35S]sulfate uptake compared with that of control twin fetuses, but uptake was not increased to values that occurred spontaneously earlier in gestation. These results suggest that the decreasing rate of [35S]sulfate uptake by fetal cartilage during the last half of gestation is associated only minimally with decreasing serum sulfate levels and is most consistent with intrinsic change in resting chondrocyte metabolism during gestation.

Congenital torsion of the penis was observed in 5 newborns, 3 of whom had fathers with torsion of the penis. We believe that this common benign condition may be transmitted as an autosomal dominant trait.

We investigated the perinatal ontogenic changes in ovine serum and tissue gastrin concentration. Fetal and maternal serum gastrin levels in serums obtained from indwelling catheters in the fetal and maternal circulations and tissue gastrin levels were assessed by radioimmunoassay and immunohistochemistry. Fetal serum gastrin concentration was undetectable until the 107th day of gestation and significantly increased to levels surpassing maternal values. Neonatal serum hormone concentration continued to rise, reaching a peak during the 4th postnatal wk and decreasing after the 4th wk coincident with weaning. Maternal serum gastrin concentration did not vary during pregnancy and did not correlate with fetal serum gastrin levels. Fetal abomasal and duodenal gastrin concentrations and abomasal G-cell number increased in parallel with the developmental alterations in fetal serum hormone levels during gestation. The developmental increase in abomasal gastrin concentration was not associated with a shift in the molecular form of the hormone. These findings support the hypothesis that circulating gastrin in the fetus is of fetal origin.

Summary: The purpose of the present study was to investigate the postnatal development of lower esophageal spincter (LES) competence in the beagle and to determine the role of gastrin in LES functional ontogeny. Eleven beagle puppies taken from two litters were studied. All puppies were allowed to suckle during the first 3 postnatal wk. In the 4th wk, all puppies were weaned, and by the 5th wk only solid chow was offered. Intraluminal manometric pressure determinations were obtained in unanesthetized, unsedated puppies using twin-lumen, 1.7 mm OD, 1 mm ID polyvinyl catheters. A 12–15 min baseline period of intraluminal pressure was monitored, after which the puppies received successive doses of 0.03, 0.1, 1.0, and 8.0 μg/kg pentagastrin (PG) SC spaced at 45-min intervals. Progressive increases in LES pressure both during basal periods and during gastric contractions and in gastric fundus (GF) pressures during gastric contractions occurred during the 1st 5 weeks of life. An increase in pressure gradient between the LES and GF during gastric contraction occurred from birth through 5 wk of age. There was no response to 0.1–8.0 μg/kg PG until postnatal days 5–6 when the LES pressure gradient in the basal state increased in response to each of these doses. There was also no significant response by the LES to PG during gastric contraction until days 11–12 when all doses of PG evoked enhancement of LES pressure. These studies suggest that an increase in LES-GF intraluminal pressure gradient develops during the initial 2 postnatal wk in this species and that this development does not involve the hormone gastrin. Later, however, the pressure gradient may depend upon both age and gastrin since a two-way analysis of variance indicated that not only is LES pressure affected by postnatal age and by PG dose, but that there is an interaction between postnatal age and PG dose which is significant. By the fifth wk, there was an apparent dose-response effect in which the lower two doses produced increased LES pressure and the larger two doses produced decreased LES pressures. Speculation: Gastroesophageal reflux (GER) in some infants may occur when the developmental interplay between endogenous gastrin concentration, increasing sensitivity to gastrin by LES, and sensitivity to gastrin by the muscular stomach proceeds abnormally. Alternatively, either the postnatal increase in LES muscle mass or the maturation of a neural pathway that mediates reflex contraction of the LES during gastric contraction, or both, may be delayed or abnormal in some children with GER. A fourth possible abnormality that may permit GER in still other infants is failure to generate the increasing gastric contraction rate and intraluminal pressures observed to occur in normal development, thus permitting delayed gastric emptying.

This investigation was performed to define certain characteristics of insulin-receptor interaction during the last 2 months of gestation in fetal sheep liver and kidney. Twenty-one sheep carrying a total of 46 fetuses were sacrificed at various gestational ages from 94 days to term; fetal and maternal livers and kidneys were analyzed by a radioreceptor assay for insulin binding characteristics. Specific binding of insulin to partially purified ovine fetal liver and kidney plasma membranes increased as gestation approached term, at which time specific binding was two- to fourfold greater to fetal than to maternal tissues. Associated with increased specific binding were late gestational increases in affinity of insulin for receptors in both fetal liver and kidney and an earlier increase in insulin receptor concentration in fetal kidney. These observations in fetal sheep liver and kidney are similar to reported observations in other species. However, the increase in specific binding of insulin to male fetal liver membranes was exponential; in contrast, there was no apparent increase in specific binding to female fetal liver membranes during the gestational interval surveyed. Both the weights and the vertebral column lengths of these fetuses were shown by multivariate analysis to be significantly affected by the interaction between specific binding of insulin and fetal sex. However, in 30 additional sheep fetuses we observed no difference between male and female fetuses in the increase with time in liver glycogen content. The lack of sex difference in this postreceptor event is consonant with the demonstrated dissociation between liver insulin receptors and glycogen synthesis in the late fetal rat. Our observations suggest that late gestational differences between male and female sheep fetuses in insulin specific binding to liver and, possibly, to other tissues such as cartilage, muscle, and/or fat, that are coupled to postreceptor events may account for differences in fetal growth between the sexes.

The effect of estradiol-17β (1 μg per kilogram) on regional blood flow and cardiac output was studied by means of radionuclide-labeled microspheres in 6 nonpregnant and 13 pregnant ewes five to seven days after operation. Estradiol caused vasodilation in myometrium, endometrium, and placental cotyledons throughout pregnancy, but these responses were significantly less than the fifteenfold increase seen in the nonpregnant uterine tissues. Significant vasodilation also occurred in the ovaries, cervix, vagina, uterine tubes, mammary gland, skin, and adrenal glands of pregnant ewes. Cardiac output increased by 14 per cent. No significant change in uterine oxygen consumption was associated with the increase in blood flow to the pregnant uterus.

Extract: Glucose/oxygen quotients were determined across the hindlimbs of seven fetuses, for a total of five studies in fetuses of fed ewes and five studies in fetuses of fasted ewes. The glucose/oxygen quotient was found to be a function of the fetal arterial glucose concentration in mM, [a], described by the equation: glucose/oxygen quotient = - 0.047 + 1.46[a]. The dependence of glucose uptake by the fetal hindlimb upon arterial glucose concentration is the first demonstration of the effect of substrate availability on the metabolism of a fetal organ. Speculation: The demonstration of glucose/oxygen quotients of 1.0 or greater for fetal tissues at a time in gestation when the umbilical glucose/oxygen quotient is 0.4–0.5 suggests two possible explanations: (1) there may be substrate specificity for oxidative metabolism for each fetal organ, and (2) non-glucose substrates such as amino acids taken up by the umbilical circulation may be utilized by the fetal liver for gluconeogenesis.

As participants in the clinical field trials in the United States for the Roche 5301 transcutaneous oxygen monitor, we report here the results of our experience for comparison with that reported by Meith and colleagues in an earlier Letter (Pediatrics 58: 299, August 1976). The Roche model 5301 differs from the previously tested model 5300 in that the oxygen sensor has been modified and the electrode operates at 44 C instead of 42 C. Thirty-two newborn infants of 28 to 39 weeks' gestational age and 560 to 3,700 gm birth weight were monitored while they experienced respiratory illness caused by idiopathic respiratory distress syndrome, pneumonia, or apnea.

To determine the relationship between fetal and maternal plasma insulin concentrations (If, Im) and umbilical uptake of glucose (Qg) and lactate (Ql) in sheep, 6 ewes of 120-130 days gestation were prepared with indwelling catheters in the umbilical vein, fetal pedal artery and vein, and maternal uterine and femoral arteries. Fed state Qg, Ql, If, and I were determined at intervals from the 2nd to the 11th postoperative day (POD). Qg and Ql were determined by the Fick principle employing steady state diffusion of antipyrine to determine umbilical blood flow. Studies were performed before (control n=15) and after (n=15) the perfusion of the uterine artery with ovine insulin 7.5 mU/kg ewe/30 min. Insulin was measured by radioimmunoassay. Results: Control If and Im in μ U/ml increased with increasing POD as described by the following regression equations: If = 0.76 POD + 3.74, (F ratio, p < .025), and Im = 1.86 POD + 8.61, (p < .05). Uterine artery insulin infusion increased Im but did not affect If or Ql. The postoperative increase in If from 5.5-16.0μ μ U/ml was associated with a decrease in Ql in mM/min/kg fetus: Ql = -0.004 If + 0.072 (p < .025). Qg was unrelated to POD, Ql, or If. Conclusions: These studies (1) confirm the lack of ovine insulin transfer across the ovine placenta in vivo, (2) demonstrate increasing Im and If for as long as 11 days after surgery and resumption of maternal nutrition, and (3) show that umbilical lactate uptake is inversely related to fetal plasma insulin concentration, but is independent of umbilical glucose uptake and of maternal plasma insulin concentration.

• The osmolalities of breast milk and of 36 products that may be fed to infants were determined by the freezing-point depression method. A wide range of osmolality was observed among formulas that provide 67 kcal/100 ml, and many have osmolalities greater than 400 mOsm/kg of water. Reconstituted powdered formulas have osmolalities that are widely varied from batch to batch, are greater when prepared by scoop measures when the osmolalities of corresponding ready-to-feed formulas, and are greater than the osmolalities of the formulas prepared by weighed measures from the manufacturer's formulation. The osmolality of products for oral consumption should be considered in the selection of formulas for preterm infants. ( Am J Dis Child 131:139-141, 1977)

Recent studies of fetal sheep metabolism in unstressed preparations have suggested that amino acids (AA) may furnish up to 25% of the substrate for fetal aerobic metabolism after 125 days gestational age (GA). This investigation was performed to determine throughout gestation the activities in fetal sheep liver and kidney of key enzymes for gluconeogenesis. Tissue specimens from 10 fetuses of well-nourished ewes at 44-145 d. GA were assayed by spectrophotometric methods. Results: (1) After 125 d. GA substantial activities were found in both liver and kidney for glucose-6-p'tase (G6P), fructose-1,6-dipTtase (F1,6DP), pyruvate carboxylase, PEP carboxykinase, aspartate aminotransferase (asp AT), and alanine aminotransferase (ala AT). The activity in kidney for each enzyme except asp AT was comparable to or greater than the activity in liver.(2) Activities of 2 enzymes increased with gestation: Conclusion: Significant activities of these enzymes in late gestation support the theories of fetal utilization of AA (a) as substrate for aerobic metabolism, and (b) for gluconeogenesis. Speculations: (1) Increasing capability for gluconeogenesis may occur as gestation proceeds. (2) The role of the kidney in overall fetal metabolism may be substantial. (* μM Pi produced/min/g. protein; x ± SEM)

The postnatal development of gastric motility and pH, and the response to pentagastrin (PG) were studied at 10 intervals in 5 beagles from birth to 6 weeks. Motility was monitored using twin single lumen 1.7 mm catheters with 1 mm side openings at the tips which were 2 cm apart. Catheters were perfused with distilled H2O at a constant rate and pressure transducers were interposed in the system. Oral catheter insertion distance to the antrum of the stomach was determined radiographically. Puppies were fasted 3-6 hours prior to study; gastric contents were aspirated, and the stomach rinsed with distilled H2O. After an initial gastric pH determination and a 10-20 min. period of baseline motility monitoring, the response to 8 μ g/kg of s.c. PG was determined. Baseline mean antral contractions increased from 0.25/min on day 1 to 2.0/min on day 1 through weaning in the 4th week when the frequency decreased to 6.0 until day 7 when mean pH was 3.4. PG produced a significant decrease in pH on day 3 (p < 0.05), but the maximum decrease did not appear until day 9 and thereafter (p < 0.005). PG inhibition of the frequency and force of antral contractions was apparent from the 3rd day through the 6th week. These observations in beagle puppies suggest a developmental maturation in gastric motility and acid secretion from birth through the 2nd week, and a delay in responsiveness to PG.