Opportunistic dried blood spot sampling validates and optimizes a pediatric population pharmacokinetic model of metronidazole.

Pharmacokinetic models rarely undergo external validation in vulnerable populations such as critically ill infants, thereby limiting the accuracy, efficacy, and safety of model-informed dosing in real-world settings. Here, we describe an opportunistic approach using dried blood spots (DBS) to evaluate a population pharmacokinetic model of metronidazole in critically ill preterm infants of gestational age (GA) ≤31 weeks from the Metronidazole Pharmacokinetics in Premature Infants (PTN_METRO, NCT01222585) study. First, we used linear correlation to compare 42 paired DBS and plasma metronidazole concentrations from 21 preterm infants [mean (SD): post natal age 28.0 (21.7) days, GA 26.3 (2.4) weeks]. Using the resulting predictive equation, we estimated plasma metronidazole concentrations (ePlasma) from 399 DBS collected from 122 preterm and term infants [mean (SD): post natal age 16.7 (15.8) days, GA 31.4 (5.1) weeks] from the Antibiotic Safety in Infants with Complicated Intra-Abdominal Infections (SCAMP, NCT01994993) trial. When evaluating the PTN_METRO model using ePlasma from the SCAMP trial, we found that the model generally predicted ePlasma well in preterm infants with GA ≤31 weeks. When including ePlasma from term and preterm infants with GA >31 weeks, the model was optimized using a sigmoidal Emax maturation function of postmenstrual age on clearance and estimated the exponent of weight on volume of distribution. The optimized model supports existing dosing guidelines and adds new data to support a 6-hour dosing interval for infants with postmenstrual age >40 weeks. Using an opportunistic DBS to externally validate and optimize a metronidazole population pharmacokinetic model was feasible and useful in this vulnerable population.

Primary hemostasis in neonates with thrombocytopenia.

OBJECTIVE: To evaluate the relationship between platelet counts and the platelet function analyzer-100 closure times (CTs) in neonates with thrombocytopenia, and to determine what other factors significantly affect CTs. STUDY DESIGN: In a single institution prospective cross-sectional study, blood samples from neonates with platelet counts <150 × 10(9)/L were tested on the platelet function analyzer-100 with CT-collagen/epinephrine (CT-Epi) and CT-collagen/adenosine diphosphate (CT-ADP) cartridges. RESULTS: The mean platelet count was 95 ± 28 × 10(9)/L for 48 infants with a mean gestational age 30.9 ± 5.3 weeks and median postnatal age of 5 (3-18) days. No association was evident between CT-Epi and platelet count. However, the CT-ADP was prolonged in many (but not all) infants with platelet counts <90 × 10(9)/L. Among infants <32 weeks gestational age, we found a moderate negative correlation between CT-ADP and platelet count (r = -0.54, P = .0045). The negative correlation was strongest in infants <32 weeks and <10 days old (r = -0.8, P = .0017). Other variables examined (hematocrit, infection, Score of Neonatal Acute Physiology II) did not have a significant effect on CT-ADP in a linear regression model. CONCLUSIONS: Platelet counts <90 × 10(9)/L are associated with prolonged CT-ADP times in some but not all infants. Gestational and postnatal age-related differences in platelet function account for some of this variability. The predictive value of CT-ADP on neonatal bleeding risk remains to be studied.

Matthew-Wood Syndrome in Monochorionic, Diamnionic Twins.

Matthew-Wood syndrome represents a rare genetic disorder characterized by diaphragmatic defects, pulmonary hypoplasia, micro- or anophthalmia, and cardiac defects. Most cases are lethal with very few infants living beyond a few years of life. Siblings with this diagnosis have been reported but never twins. In this article, we provided a review and discussion of this syndrome following its presentation in monochorionic, diamnionic twin females.

The frequency and timing of sepsis-associated coagulopathy in the neonatal intensive care unit.

Introduction: Sepsis is a common cause of morbidity and mortality in the neonatal intensive care unit (NICU). The frequency and severity of sepsis-associated coagulopathy as well as its relationship to illness severity are unclear. Methods: We performed a single-center, retrospective, observational cohort study of all infants admitted to the University of Florida Health (UF Health), level IV NICU between January 1st 2012 to March 1st 2020 to measure the frequency of sepsis-associated coagulopathy as well as its temporal relationship to critical illness in the NICU population. All clinical data in the electronic health record were extracted and deposited into an integrated data repository that was used for this work. Results: We identified 225 new sepsis episodes in 216 patients. An evaluation for sepsis-associated coagulopathy was performed in 96 (43%) episodes. Gram-negative pathogen, nSOFA score at evaluation, and mortality were greater among episodes that included a coagulopathy evaluation compared with those that did not. Abnormal coagulation results were common (271/339 evaluations; 80%) and were predominantly prothrombin times. Intervention (plasma or cryoprecipitate) followed a minority (84/271; 31%) of abnormal results, occurred in 40/96 (42%) episodes that were often associated with >1 intervention (29/40; 73%), and coincided with thrombocytopenia in 37/40 (93%) and platelet transfusion in 27/40 (68%). Shapley Additive Explanations modeling demonstrated strong predictive performance for the composite outcome of death and/or treatment for coagulopathy in neonates (f1 score 0.8, area under receiver operating characteristic curve 0.83 for those with abnormal coagulation values). The three most important features influencing the composite outcome of death or treatment for coagulopathy included administration of vasoactive medications, hematologic dysfunction assessed by the maximum nSOFA platelet score, and early sepsis (≤72 h after birth). Conclusions: A coagulopathy evaluation was performed in a minority of NICU patients with sepsis and was associated with greater illness severity and mortality. Abnormal results were common but infrequently associated with intervention, and intervention was contemporaneous with thrombocytopenia. The most important feature that influenced the composite outcome of death or treatment for coagulopathy was the administration of vasoactive-inotropic medications. These data help to identify NICU patients at risk of sepsis-associated coagulopathy.

Severe Thromboses in Neonates.

Severe thrombosis in the neonate presents a diagnostic challenge to the clinician as the benefits and risks for treatment must be weighed with every medical decision. Aortic thromboses, large right atrial thromboses, and septic thrombophlebitis present unique clinical challenges that must be managed in the appropriate clinical setting with appropriate subspecialty support. Unfortunately, there is limited data on what the ideal therapy should be for these specific types of cases. In this review, we will discuss these types of severe thromboses that may occur in neonates and potential therapies that may offer benefits.

Postnatal treatment for children with fetal and neonatal alloimmune thrombocytopenia: a multicentre, retrospective, cohort study.

BACKGROUND: Children affected by fetal and neonatal alloimmune thrombocytopenia (FNAIT) are at risk of severe intracranial haemorrhage. Management in the postnatal period is based on sparse evidence. We aimed to describe the contemporary management and outcomes of patients with FNAIT in high-income countries. METHODS: In this multicentre, retrospective, cohort study, we set up a web-based registry for the collection of deidentified data on the management and course of neonates with FNAIT. Eight centres from seven countries (Australia, Norway, Slovenia, Spain, Sweden, the Netherlands, and the USA) participated. Eligibility criteria comprised neonates with FNAIT being liveborn between Jan 1, 2010, and Jan 1, 2020; anti-human platelet antigen (HPA) alloantibodies in maternal serum; confirmed maternal and fetal HPA incompatibility; and bleeding detected at antenatal ultrasound, neonatal thrombocytopenia (<150 × 109 platelets per L), or both in the current or previous pregnancy. Clinical data were retrieved from local medical records of the first neonatal admission and entered in the registry. The key outcome was the type of postnatal treatment given to neonates with FNAIT. Other outcomes were daily median platelet counts in the first week of life, median platelet count increment after first unmatched versus first matched transfusions, and the proportion of neonates with mild or severe bleeding. FINDINGS: 408 liveborn neonates with FNAIT were entered into the FNAIT registry, of whom 389 from Australia (n=74), Norway (n=56), Slovenia (n=19), Spain (n=55), Sweden (n=31), the Netherlands (n=138), and the USA (n=16) were included in our analyses. The median follow-up was 5 days (IQR 2-9). More neonates were male (241 [64%] of 379) than female (138 [36%]). Severe thrombocytopenia (platelet count <50 × 109 platelets per L) was reported in 283 (74%) of 380 neonates, and extreme thrombocytopenia (<10 × 109 platelets per L) was reported in 92 (24%) neonates. Postnatal platelet count nadir was higher in the no-treatment group than in all other groups. 163 (42%) of 389 neonates with FNAIT received no postnatal treatment. 207 (53%) neonates received platelet transfusions, which were either HPA-unmatched (88 [43%] of 207), HPA-matched (84 [41%]), or a combination of both (35 [17%]). The proportion of neonates who received HPA-matched platelet transfusions varied between countries, ranging from 0% (Slovenia) to 63% (35 of 56 neonates; Norway). Postnatal intravenous immunoglobulin treatment was given to 110 (28%) of 389 neonates (alone [n=19] or in combination with platelet transfusions [n=91]), with the proportion receiving it ranging from 12% (17 of 138 neonates; the Netherlands) to 63% (ten of 16 neonates; the USA) across countries. The median platelet increment was 59 × 109 platelets per L (IQR 35-94) after HPA-unmatched platelet transfusions and 98 × 109 platelets per L (67-134) after HPA-matched platelet transfusions (p<0·0001). Severe bleeding was diagnosed in 23 (6%) of 389 liveborn neonates, with one having a severe pulmonary haemorrhage and 22 having severe intracranial haemorrhages. Mild bleeding was diagnosed in 186 (48%) neonates. INTERPRETATION: Postnatal management of FNAIT varies greatly between international centres, highlighting the absence of consensus on optimal treatments. Our data suggest that HPA-matched transfusions lead to a larger median platelet count increment than HPA-unmatched transfusions, but whether HPA matching is also associated with a reduced risk of bleeding remains unknown. FUNDING: Sanquin.

Antibiotic Safety and Effectiveness in Premature Infants With Complicated Intraabdominal Infections.

BACKGROUND: In premature infants, complicated intraabdominal infections (cIAIs) are a leading cause of morbidity and mortality. Although universally prescribed, the safety and effectiveness of commonly used antibiotic regimens have not been established in this population. METHODS: Infants ≤33 weeks gestational age and <121 days postnatal age with cIAI were randomized to ≤10 days of ampicillin, gentamicin, and metronidazole (group 1); ampicillin, gentamicin, and clindamycin (group 2); or piperacillin-tazobactam and gentamicin (group 3) at doses stratified by postmenstrual age. Due to slow enrollment, a protocol amendment allowed eligible infants already receiving study regimens to enroll without randomization. The primary outcome was mortality within 30 days of study drug completion. Secondary outcomes included adverse events, outcomes of special interest, and therapeutic success (absence of death, negative cultures, and clinical cure score >4) 30 days after study drug completion. RESULTS: One hundred eighty infants [128 randomized (R), 52 nonrandomized (NR)] were enrolled: 63 in group 1 (45 R, 18 NR), 47 in group 2 (41 R, 6 NR), and 70 in group 3 (42 R, 28 NR). Thirty-day mortality was 8%, 7%, and 9% in groups 1, 2, and 3, respectively. There were no differences in safety outcomes between antibiotic regimens. After adjusting for treatment group and gestational age, mortality rates through end of follow-up were 4.22 [95% confidence interval (CI): 1.39-12.13], 4.53 (95% CI: 1.21-15.50), and 4.07 (95% CI: 1.22-12.70) for groups 1, 2, and 3, respectively. CONCLUSIONS: Each of the antibiotic regimens are safe in premature infants with cIAI. CLINICAL TRIAL REGISTRATION: NCT0199499.

Gastroschisis with jejunal and colonic atresia, and isolated colonic atresia in dichorionic, diamniotic twins.

Despite the increasing incidence of gastroschisis, the cause remains unknown. Genetic factors may contribute to bowel anomalies as demonstrated by cases of gastroschisis in twins and siblings, and other types of bowel anomalies in twins. Atresia of the colon represents one of the rarest causes of neonatal intestinal obstruction. We present the first case of dichorionic, diamniotic male twins in which there was gastroschisis with jejunal and colonic atresia in Twin A and isolated colonic atresia in Twin B.

Effects of sepsis on neonatal thrombopoiesis.

We serially evaluated the effects of sepsis and/or necrotizing enterocolitis (NEC) on neonatal thrombopoiesis, using a panel of tests that included platelet counts, thrombopoietin concentrations (Tpo), circulating megakaryocyte progenitor concentrations (CMPs), and reticulated platelets (RPs). Variables analyzed included sepsis type, time after onset of sepsis, platelet counts, and gestational (GA) and postconceptional ages (PCA). Twenty neonates were enrolled. Ten had Gram-negative, six had Gram-positive, and four had presumed sepsis. Four neonates had NEC stage II or higher, and six developed thrombocytopenia. Overall, septic neonates had significantly elevated Tpo concentrations and circulating megakaryocyte progenitors. The highest Tpo levels were associated with Gram-negative or presumed sepsis. RP percentages were increased only in neonates with low platelet counts, while RP counts (RP% x platelet count) were elevated in neonates with high platelet counts. Our findings suggest that septic neonates up-regulate Tpo production, leading to increased megakaryocytopoiesis and platelet release, although the degree of upregulation is moderate. The changes in RP% and RP count most likely reflect increased thrombopoiesis with variable degrees of platelet consumption. In addition, our findings suggest that different factors, likely including level of illness and/or specific platelet or bacterial products, can down-regulate the magnitude of the thrombopoietic response.

Neonatal thrombocytopenia: what we do and don't know.

The evaluation and management of thrombocytopenia is a frequent challenge for neonatologists, as it affects 22-35% of infants admitted to the neonatal intensive care unit. Multiple disease processes can cause neonatal thrombocytopenia, and these can be classified as those inducing early thrombocytopenia (< or =72 h of life) and those inducing late-onset thrombocytopenia (>72 h). Most cases of neonatal thrombocytopenia are mild to moderate, and do not warrant intervention. In approximately 25% of affected neonates, however, the platelets count is <50 x 10(9)/L, and therapy with platelet transfusions is considered to decrease the risk of hemorrhage. The existing evidence to establish platelet transfusion triggers in neonates is very limited, but it suggests that transfusing platelets to non-bleeding neonates with platelet counts >50 x 10(9)/L does not decrease the risk of intraventricular hemorrhage (IVH), and that 30 x 10(9)/L might be an adequate threshold for stable non-bleeding neonates. However, adequately powered multi-center studies are needed to conclusively establish the safety of any given set of neonatal transfusion guidelines.

Treatment of Severe Native Left Pulmonary Artery Stenosis With Coronary Stent Implantation in a 2.4 kg Neonate.

A 1-month-old, 2.4 kg infant, previously born at 32 weeks gestation, was found to have a murmur while in the neonatal intensive care unit. The patient had ongoing feeding intolerance and required supplemental oxygen via nasal cannula. Cardiac computed tomography showed discrete stenosis of the proximal left pulmonary artery (LPA) with a normal-sized distal LPA. We describe the treatment course with transcatheter coronary stent implantation.

Platelet Transfusion Practices Among Very-Low-Birth-Weight Infants.

IMPORTANCE: Thrombocytopenia and intraventricular hemorrhage (IVH) are common among very-low-birth-weight (VLBW) infants. Survey results suggest that US neonatologists frequently administer platelet transfusions to VLBW infants with mild to moderate thrombocytopenia. OBJECTIVES: To characterize platelet transfusion practices in US neonatal intensive care units (NICUs), to determine whether severity of illness influences platelet transfusion decisions, and to examine the association between platelet count (PCT) and the risk for IVH in the first 7 days of life. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, retrospective cohort study included 972 VLBW infants treated in 6 US NICUs, with admission dates from January 1, 2006, to December 31, 2007. Data were collected from all infants until NICU discharge or death (last day of data collected, December 4, 2008). Data were entered into the central database, cleaned, and analyzed from May 1, 2009, to February 11, 2016. INTERVENTION: Platelet transfusion. MAIN OUTCOMES AND MEASURES: Number of platelet transfusions and incidence of IVH. RESULTS: Among the 972 VLBW infants (520 [53.5%] male; mean [SD] gestational age, 28.2 [2.9] weeks), 231 received 1002 platelet transfusions (mean [SD], 4.3 [6.0] per infant; range, 1-63 per infant). The pretransfusion PCT was at least 50 000/µL for 653 of 998 transfusions (65.4%) with this information. Two hundred eighty-one transfusions (28.0%) were given during the first 7 days of life. During that period, platelet transfusions were given on 35 of 53 days (66.0%) when the patient had a PCT less than 50 000/µL and on 203 of 436 days (46.6%) when the patient had a PCT of 50 000/µL to 99 000/µL. At least 1 marker of severe illness was present on 198 of 212 patient-days (93.4%) with thrombocytopenia (PCT, <100 000/µL) when a platelet transfusion was given compared with 113 of 190 patient-days (59.5%) with thrombocytopenia when no platelet transfusion was given. Thrombocytopenia was a risk factor for intraventricular hemorrhage during the first 7 days of life (hazard ratio, 2.17; 95% CI, 1.53-3.08; P < .001). However, no correlation was found between severity of thrombocytopenia and risk for IVH. After controlling for significant clinical factors and thrombocytopenia, platelet transfusions did not have a significant effect on the incidence of IVH (hazard ratio, 0.92; 95% CI, 0.49-1.73; P = .80). CONCLUSIONS AND RELEVANCE: A large proportion of platelet transfusions were given to VLBW infants with PCT greater than 50 000/µL. Severity of illness influenced transfusion decisions. However, the severity of thrombocytopenia did not correlate with the risk for IVH, and platelet transfusions did not reduce this risk.

Neonatal hypothalamic hamartoma: a differentiating nonlethal hamartoblastoma.

The authors report on a patient with a large hypothalamic hamartoma with a cleft lip and palate and seizures. Neuroimaging revealed a large extraaxial, intradural mass in the prepontine and interpeduncular cisterns with significant distortion of the brainstem. A stereotactic transfontanel needle biopsy revealed a cellular lesion that contained immature-appearing neuroepithelial cells consistent with prior descriptions of hypothalamic hamartoblastoma. While having a low level of proliferation by Ki67 (MIB-1) labeling, the lesion also contained evidence of neuronal maturation, with many cells expressing neuronal nuclear antigen as observed during immunohistochemical analysis. Further clinical evaluation revealed no other significant congenital abnormalities, and the patient was discharged home. Outpatient follow up has continued for 2 years and the patient has been doing well, requiring no further treatment. This case illustrates that, despite its immature and proliferative histological appearance, this rare neonatal mass can be regarded as a "differentiating" hypothalamic hamartoma and can have a favorable prognosis.

Thrombosis in the Neonatal Intensive Care Unit.

Neonates have the highest risk for pathologic thrombosis among pediatric patients. A combination of genetic and acquired risk factors significantly contributes to this risk, with the most important risk factor being the use of central venous catheters. Proper imaging is critical for confirming the diagnosis. Despite a significant number of these events being life- and limb-threatening, there is limited evidence on what the appropriate management strategy should be. Evaluation and treatment of any neonate with a clinically significant thrombosis should occur at a tertiary referral center that has proper support.

Primary antiphospholipid syndrome presenting with a branch retinal artery occlusion in a 15-year-old boy.

Acute vascular events are rare in the pediatric population, but there is an association with the presence of antiphospholipid antibodies. When there is no other underlying medical disorder, this is referred to as primary antiphospholipid syndrome. We present a case of a 15-year-old boy who developed an acute superior branch retinal artery occlusion. Complete evaluation revealed significant elevations in antiphospholipid antibodies. To our knowledge, there are no cases in children of primary antiphospholipid syndrome presenting with this clinical manifestation.

The concentration of circulating megakaryocyte progenitors in preterm neonates is a function of post-conceptional age.

Circulating megakaryocyte (Mk) progenitors have been used as a measure of megakaryocytopoiesis in neonates. Prior studies have shown a gestational age-dependent decrease in their concentration, but it is unclear how this process continues after birth in preterm neonates. To answer this question, we quantified the Mk progenitors in the blood of 42 neonates of varying post-conceptional ages (gestational age+days of life). We found an inverse relationship between concentration of circulating Mk progenitors and post-conceptional age (r=-0.54, p=0.0002).

Mucopolysaccharidosis Type VII presenting with isolated neonatal ascites.

Mucopolysaccharidosis Type VII (MPS VII) is a lysosomal storage disease caused by a deficiency of the enzyme, beta-glucuronidase. MPS VII has a wide variation in phenotypic expression, including presentation in the neonatal period with nonimmune hydrops fetalis. We report a neonate with MPS VII who initially presented with marked isolated ascites not associated with hydrops fetalis. This appears to be a novel finding in patients with MPS VII.