Infant Dose Research Articles

Remdesivir and Human Milk: A Case Study.

Remdesivir was originally developed to treat Ebola hemorrhagic fever, and its efficacy in treating coronavirus disease 2019 was detected during a preliminary analysis of a randomized controlled trial. It is known that Severe Acute Respiratory Syndrome Coronavirus 2 is not transmitted through human milk, but data about the presence of remdesivir in human milk have been lacking. In this case study, we determined the human milk-to-serum drug concentration ratio and the relative dose of Remdesivir in one participant. The participant, a 28-year-old primipara, was found to have Coronavirus 2 infection in 2019, 2 days after delivery. She was given Remdesivir. The Remdesivir concentration in maternal serum and human milk was measured, and the milk-to-serum drug concentration ratio was found to be low (0.089), as was the relative infant dose (0.0070). The participant could not breastfeed her infant during her Coronavirus 2 infection treatment because in Japan anyone with COVID-19 was completely quarantined. However, she was able to resume breastfeeding after discharge and breastfed her infant for 6 months with supplements. Given the low amount of Remdesivir in the participant's milk, the inclusion of antibodies to Severe Acute Respiratory Syndrome Coronavirus 2, which can be expected to protect the infant from infection, and various other benefits of human milk, suggests that breastfeeding is safe during treatment with Remdesivir.

Peginterferon beta-1a concentrations in breast milk of lactating multiple sclerosis patients

BackgroundPeginterferon beta-1a is an interferon beta-1a formulation that has been pegylated, resulting in a longer half-life than other interferon beta formulations. We examined concentrations of peginterferon beta-1a in breast milk of lactating patients with multiple sclerosis (MS) receiving peginterferon beta-1a as their postpartum disease-modifying therapy. MethodsAfter completion of titration to a full dose of peginterferon beta-1a and following a single full dose peginterferon beta-1a injection (125 µg), breast milk samples (≥10 mL) were collected by 5 women on days 1–14 post injection. Peginterferon beta-1a concentrations in breast milk samples were measured by a qualified enzyme-linked immunosorbent assay (detection threshold: 15 pg/mL). Mean and median daily concentrations and median maximum concentration (Cmax), time of Cmax (Tmax), time of last measurable concentration (Tlast), area under the concentration-time curve (AUClast), and relative infant dose (RID) were determined. ResultsAfter receiving a single full dose peginterferon beta-1a injection, the maximum breast milk concentration recorded in an individual patient was 126.2 pg/mL (0.00013 µg/mL) on day 6. The remaining patients all had maximum breast milk concentrations <72 pg/mL. The geometric mean of Cmax was 48.9 pg/mL and the median Tmax and Tlast were 4 and 7 days, respectively. The median AUClast was 210.9 day*pg/mL. Among the 5 study patients, the mean breast milk concentration across all study days was 35.95 pg/mL, with an estimated RID of 0.0054% of the maternal dose. ConclusionMinimal concentrations of peginterferon beta-1a were detected in the breast milk samples. These findings may be useful for clinicians considering postpartum MS treatment options.

Measurement of age-dependent radiation ingestion doses due to gross alpha and gross beta exposure from medicinal plants

ABSTRACT This article presents the results of a study conducted to measure the gross alpha, gross beta activities in medicinal plant samples collected from different districts of Azad Kashmir, Pakistan. The ASC-950-DP gasless high-speed counter was used for the measurement of gross α/β activities. Measured activities have been used to assess age-dependent annual effective doses for infants, one-, five-, ten-, and fifteen-year-old and adult people. For a medicinal plant consumption rate (MPCR) of 1.8 kg a–1, the average gross alpha and beta annual committed effective dose (ACED) delivered to one-, five-, ten-, fifteen-year-olds and adults fall below the WHO recommended level (290 µSv a–1) and that reported in the UNSCEAR 2000 (0.3 mSv a–1) report. Results obtained for the current study show that the radiological hazard related to the consumption of natural radionuclides in medicinal plants is inconsequential with exception of the ACED delivered to infants at an MPCR of 1.8 g a–1 and higher values.

Antibody persistence and immune memory response following primary vaccination and boosting with live attenuated SA 14-14-2 Japanese encephalitis vaccine (CD-JEV) in Bangladesh: A phase 4 open-label clinical trial

IntroductionJapanese encephalitis (JE) virus is one of the leading causes of viral encephalitis across temperate and tropical zones of Asia. The live attenuated SA 14-14-2 JE vaccine (CD-JEV) is one of three vaccines prequalified by the World Health Organization (WHO) to prevent JE. WHO currently recommends a single CD-JEV dose for infants in endemic settings. However, in the absence of long-term immunogenicity data, WHO has indicated a need for long-term immunogenicity studies to inform optimal dosing schedules and determine the need for booster doses. MethodsThis Phase 4, open-label clinical study measured neutralizing antibody (NAb) titers in Bangladeshi children three and four years after primary CD-JEV vaccination and 7 and 28 days after a booster CD-JEV vaccination given four years after primary vaccination. The study also assessed the tolerability and safety of the booster dose. A NAb titer of ≥1:10 was considered seroprotective. ResultsOf 560 children vaccinated between 10 and 12 months of age with CD-JEV three years earlier and enrolled in this study from 30 July 2015 through 03 January 2016, 52 (9.3%; 95% CI: 7.2–12.0) had a seroprotective titer at enrollment. One year later, of 533 children, 66 (12.4%; 95% CI: 9.9–15.5) had a seroprotective titer before receiving a booster dose. Of 524 children who received a booster CD-JEV dose, 479 (91.4%; 95% CI: 88.7–93.5) and 514 (98.1%; 95% CI: 96.5–99.0) were seroprotected 7 and 28 days later, respectively. The geometric mean titer (GMT) was 6 (95% CI: 6–6) at baseline, 105 (95% CI: 93–119) 7 days post-booster, and 167 (95% CI: 152–183) 28 days post-booster. No vaccine-associated neurologic adverse events or other serious adverse events were noted following the booster dose. ConclusionsAlthough most children did not have measurable antibody titers three and four years after a single primary CD-JEV dose, more than 90% of seronegative children had a strong anamnestic response within one week of a booster dose. This suggests that these children were immune despite the absence of measurable NAb prior to their booster.ClinicalTrials.gov Identifier: NCT02514746.

Product review on the IMD serogroup B vaccine Bexsero®

ABSTRACT Bexsero® is a multicomponent vaccine composed of four major proteins of Neisseria meningitidis: the fHbp, NHBA, NadA and PorA. This vaccine was licensed against invasive meningococcal disease (IMD) due to serogroup B isolates. When administered alone, Bexsero® showed a safety profile similar to other childhood vaccines. It provides an excellent immunogenicity but that requires booster doses in infants and young children. Although the vaccine does not seem to impact on acquisition of carriage of serogroup B isolates, it confers protection against isolates of serogroup B harboring distinct but cross-reactive variants of fHbp, NadA and NHBA. Primary vaccination schemes in infancy underwent a rapid increase after a toddler booster suggesting an anamnestic response and the establishment of a memory response. As Bexsero® targets sub-capsular proteins that can be conserved regardless the capsule, the vaccine can be effective against non-B isolates such as isolates of serogroups W and X.

Pertussis burden and acellular pertussis vaccine effectiveness in high risk children

BackgroundPertussis hospitalisation is more common among infants born prematurely, who have significant comorbidities, or are Indigenous, but acellular pertussis (aP) vaccine effectiveness (VE) estimates in these sub-groups are lacking. We measured aP VE by Indigenous status, and policy-relevant categories of prematurity and comorbidity, in a population-based Australian cohort. MethodsPerinatal, disease notification, hospitalisation, mortality, and vaccination data were linked to birth records in two Australian states (Western Australia and New South Wales) 2001–2012, with follow-up to the end of 2013. Children followed to 18 months of age were stratified by Aboriginality, prematurity (<32 vs 32–<37 weeks gestation) and comorbidities identified from hospital discharge coding. Rates, rate ratios and VE were calculated for first episode of hospitalised and non-hospitalised pertussis notifications using adjusted Cox proportional hazards models. ResultsAmong >1,300,000 children, 63,867 (4·9%) were Aboriginal, 47,721 (3·6%) had at least one comorbidity and 3,771 first episodes of notified pertussis occurred <18 months of age; of these, 1,207 (32.0%) had an associated pertussis-coded hospitalisation. For hospitalised pertussis in Aboriginal and non-Aboriginal children, there was significant protection post dose 1 (VE 51% v 25%), 2 (VE 69% v 74%) and 3 (VE 76% v 80%). For children with co-morbidities, VE for hospitalised pertussis was low and non-significant post dose 1 (0%) and 2 (30%). Post dose 3, VE was significant for hospitalised pertussis (70%; 95% CI 29–87) but not for non-hospitalised pertussis (24%; 95% CI −49 to 61). ConclusionsFor most Aboriginal and non-Aboriginal children, improved timeliness of current infant doses and higher antenatal coverage should further improve protection against pertussis of any severity. For children at highest risk of severe pertussis (born <32 weeks gestation or with significant medical comorbidities), our data suggest that additional measures-such as extra doses of pertussis-containing vaccines and/or vaccines with improved immunogenicity–are needed for protection.

Magnitude of Lamotrigine Exposure Through Breastfeeding.

Importance: Lamotrigine use during breastfeeding has significantly increased in the recent years, whereas breast milk lamotrigine pharmacokinetics data are still sparse. Objectives: To assess lamotrigine exposure in breastfed infants by monitoring maternal serum and breast milk concentrations. Methods: Breastfeeding women treated with lamotrigine were recruited to this study. Maternal trough breast milk and serum samples were collected, and additional breast milk samples were collected 1, 3, 6, 9, 12 hours after lamotrigine consumption. Trough breast milk/serum ratios (M/S ratio) and breast milk area under the curve (AUC) values were calculated. Results: Twenty-one breastfeeding women were recruited to this study, and the final dataset was based on the samples collected from 17 women. Lamotrigine trough serum and mother's milk concentrations were 5.1 ± 3.3 mg/L and 3.1 ± 1.9 mg/L, respectively (mean ± standard deviation). The trough M/S ratio of lamotrigine was 0.66 ± 0.22. The lamotrigine breast milk average AUC was 41.7 ± 24.6 mg·h/L. The estimated infant dose of lamotrigine was 0.52 ± 0.31 mg/kg/day and 0.26 ± 0.15 mg/kg/day for fully and partially breastfed infants, respectively. Significant correlation was found between the maternal lamotrigine serum trough concentrations and the breast milk parameters: trough breast milk concentrations (Spearman's rho = 0.986, p < 0.0001) and breast milk AUC values (Spearman's rho = 0.941, p < 0.0001). No significant correlation was found between the maternal lamotrigine daily dose and serum trough concentrations, breast milk trough concentrations, and breast milk AUC values (Spearman's rho = 0.294, 0.285, and 0.438, p = 0.252, 0.396, and 0.078, respectively). Conclusion and Relevance: High correlation between the maternal lamotrigine trough serum concentrations and the breast milk AUC values was found, implying that monitoring the maternal lamotrigine serum concentrations can be useful for prediction of exposure of infants to lamotrigine through the breast milk. The trial was registered in the Israeli trials registry MOH_2021-09-05_010243 at September 5, 2021 Retrospectively registered https://my.health.gov.il/CliniTrials.

Human Milk and Plasma Pharmacokinetics of Single-Dose Rimegepant 75 mg in Healthy Lactating Women.

Objective:Investigate whether rimegepant—an oral small molecule calcitonin gene-related peptide receptor antagonist for the treatment of migraine—is excreted in human milk after a single 75 mg dose and characterize its concentration–time profile in the plasma and milk of healthy lactating women to determine the relative infant dose (RID).Methods:This open-label, single-center study enrolled healthy lactating women aged 18–40 years with a gestation of 37–42 weeks and uncomplicated delivery of a single healthy child ≥2 weeks (14 days) and ≤6 months before study drug administration. Plasma samples were collected 0, 1, 2, 4, and 8 hours postdose; human milk samples were collected at 0, 1, 2, 4, 8, 12, 16, 24, 32, and 36 hours. The milk:plasma drug concentration ratio was estimated as the ratio of the human milk:plasma areas under the curve. The RID (%) was calculated as 100 times the quotient of the body weight-normalized infant and maternal doses.Results:Subjects (N = 12) were enrolled between 25 January and 15 September 2020. The mean (standard deviation [SD]) age was 29.8 (3.6) years; mean (SD) body mass index was 26.8 (4.9) kg/m2. The mean (SD) RID of rimegepant was 0.51% (0.14). The mean (SD) body-weight normalized infant dose was 0.005 (0.001) mg/kg/day, the mean (SD) body-weight normalized maternal dose was 1.04 (0.18) mg/kg/day, and mean (SD) maternal body weight was 74.0 (13.3) kg.Conclusion:On a weight-adjusted basis, the mean RID of rimegepant was <1% of the maternal dose.

Infant Dextromethorphan and Dextrorphan Exposure via Breast Milk From Mothers Who Are CYP2D6 Extensive Metabolizers.

The risk of infant exposure to dextromethorphan (DM) and its active metabolite, dextrorphan (DX), through breast milk has not been evaluated. In this study, bound and unbound DM and DX concentrations in breast milk and plasma at 2hours post-dose were measured in 20 lactating women (n=20) following a single 30 mg oral dose of DM. The DM and DX concentrations in breast milk were positively correlated with their respective plasma concentrations. The breast milk-to-plasma (M/P) ratios of 1.0 and 1.6 and the unbound M/P ratios of 1.1 and 2.0 for DM and DX, respectively, suggested that DM and DX are extensively distributed into breast milk. The infant exposure following a single dose of 30 mg DM was estimated using breast milk concentrations of 0.33±0.32 and 1.8±1.0μg/kg/day for DM and DX, respectively. The steady-state infant exposure was estimated using the M/P ratios and previously reported area under the concentration-time curve (AUC) of DM and DX following repeated dosing of DM 60mg orally, twice daily, to be 0.64±0.22 and 1.23±0.38μg/kg/day, respectively. Based on these estimated infant doses, the relative infant doses (RIDs) were estimated to be <1%, suggesting the infant is only exposed to a minor fraction of adult dose through breast milk; however, one nursing infant developed an erythematous rash during this study, which warrants additional research to fully elucidate the risks of infant exposure to DM and DX through breast milk.

Clinical Pharmacology of Fentanyl in Infants and Children

Fentanyl is a systemic opioid related to the phenylpiperidines, it is used in anaesthetic practice and in analgesia and the analgesic effect is about 100 times higher than that of morphine. Fentanyl is highly lipid soluble, rapidly crosses the blood-brain-barrier, and fentanyl concentrations rapidly decline in plasma and cerebrospinal fluid. Fentanyl causes respiratory depression and decreases the heart rate through vagal activation. Fentanyl may be administered intravenously, orally, by transdermal, intranasal or by buccal application and the oral bioavailability is poor. In infants, fentanyl is given for short term use, sustained use, and during therapeutic hypothermia. In children, fentanyl is given intravenously, by transdermal application, or by buccal administration and the fentanyl dose varies with the child age and body-weight. Fentanyl has been found efficacy and safe in infants and children but it may induce adverse-effects and fentanyl causes different effects in infants and children. Following intravenous administration of fentanyl to infants and children, the fentanyl elimination half-life ranges from 208 to 1,266 min and the distribution volume ranges from 1.92 to 15.2 L/kg. Such variability is due to the wide variation of subject’s demographic characteristics. Fentanyl interacts with drugs, the treatment and trials with fentanyl have been studied in infants and children. Fentanyl freely crosses the human placenta and poorly migrates into the breast-milk. The aim of this study is to review fentanyl dosing, efficacy, safety, effects, adverse-effects, metabolism, pharmacokinetics, drug interaction, treatment, and trials in infants and children, and fentanyl placental transfer and migration into the breast-milk.

Clinical Pharmacology of Rocuronium in Infants and Children

The main clinical use of the neuromuscular blocking agents is an adjuvant in surgical anaesthesia to obtain relaxation of skeletal muscle, particularly of the abdominal wall, to facilitate surgical manipulations. Rocuronium can be used instead of suxamethonium to provide rapid muscle paralysis during tracheal intubation but the recovery is much slower. Rocuronium is administered intravenously to infants and children. In infants, rocuronium is administered at a dose of 450 µg/kg for providing muscle relaxation for laryngeal intubation. To provide sustained paralysis, rocuronium is given at a dose of 600 µg/kg. In children, the neuromuscular blockade is obtained with 600 µg/kg followed by an intravenous infusion of 150 µg/kg per hour. For assisted ventilation in intensive care, rocuronium is administered at a dose of 600 µg/kg followed by an intravenous infusion of 300 to 600 µg/kg per hour. The effects of rocuronium have been extensively studied in infants and children. Rocuronium is converted into 17-desacetyl rocuronium. The pharmacokinetics of rocuronium have been studied in infants and children and the mean residence time is 55.6 and 25.6 min (P-value &lt; 0.01) in infant and children, respectively. Rocuronium interacts with drugs, the treatment of infants and children with rocuronium has been studied, and rocuronium poorly crosses the human placenta. The aim of this study is to review the published data on rocuronium dosing, pharmacokinetics, and treatment in infants and children, and rocuronium metabolism and transfer across the human placenta.

Management of Psychiatric Disorders during the Perinatal Period.

Management of Psychiatric Disorders during the Perinatal Period.

1184. A Phase 3, Multicenter, Randomized, Double-blind Study to Evaluate the Interchangeability of V114 and Prevnar 13™ with Respect to Safety, Tolerability, and Immunogenicity in Healthy Infants (PNEU-DIRECTION)

BackgroundPneumococcal diseases (PD) caused by Streptococcus pneumoniae are a major health concern globally. In children, currently licensed pneumococcal conjugate vaccines (PCVs) provide protection against PD from vaccine serotypes, but other non-vaccine serotypes have emerged and contribute to most residual disease. V114 is a 15-valent investigational PCV containing serotypes 22F and 33F in addition to the 13 serotypes shared by Prevnar 13TM (PCV13). This phase 3 study evaluated safety and immunogenicity of mixed PCV13/V114 regimens when changing from PCV13 to V114 at doses 2, 3, or 4.MethodsIn this double-blind trial, 900 infants were randomized in equal ratios to five treatment groups using a 3 + 1 immunization schedule (3-dose infant primary series followed by one toddler dose). Groups 2, 3, and 4 started with PCV13 and switched to V114 at doses 4, 3, and 2, respectively. Groups 1 and 5 received four doses of PCV13 and V114, respectively. Immunoglobulin G (IgG) responses to the 15 pneumococcal serotypes in V114 were measured at 30 days post-dose 3, prior to dose 4, and 30 days post-dose 4 (PD4). Primary immunogenicity analysis was based on 13 shared serotype responses at PD4. Safety was evaluated as the proportion of participants with adverse events (AEs). ResultsAt 30 days PD4, IgG geometric mean concentrations (GMCs) for the 13 shared serotypes were generally comparable between V114/PCV13 mixed regimens (Groups 2-4) and participants that received the 4-dose PCV13 regimen (Group 1). Additionally, IgG GMCs for the 13 shared serotypes were generally comparable for participants that received the 4-dose V114 regimen (Group 5) and participants that received the 4-dose PCV13 regimen (Group 1). Infants given at least one dose of V114 mounted immune responses to two unique serotypes in V114 (22F and 33F). Frequency of injection-site and systemic AEs among study participants were generally comparable across all study groups. ConclusionV114 was well tolerated with a generally comparable safety profile to PCV13. For the 13 shared serotypes, both mixed-dose and 4-dose regimens of V114 induced generally comparable antibody responses to a PCV13 4-dose regimen. Study results support interchangeability of V114 with PCV13 in infants.Disclosures Adroniki Bili, MD, Merck & Co., Inc. (Employee, Shareholder) Ron Dagan, MD, Medimmune/AstraZeneca (Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support)MSD (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker’s Bureau)Pfizer (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker’s Bureau) Marissa B. Wilck, MD, Merck & Co., Inc. (Employee, Shareholder) Waldimir Vallejos, MD, Merck & Co., Inc. (Employee, Shareholder) Christine Nunn, MS, Merck & Co., Inc. (Employee, Shareholder) Richard McFetridge, B.S., Merck & Co., Inc (Employee) Rong Fu, PhD, MSD China (Employee, Shareholder) Robert Lupinacci, M.S, Merck & Co., Inc (Employee, Shareholder) Luwy Musey, MD, Merck & Co., Inc. (Employee) Kara Bickham, MD, Merck Sharp and Dohme (Employee, Shareholder)

Vaccination rates and adherence in premature infants before and after pneumococcal conjugate vaccine schedule change for term infants – A claims database analysis in Germany

BackgroundIn 2015, the German Standing Committee on Vaccination (STIKO) changed the pneumococcal conjugate vaccination (PCV) schedule for mature infants from a 3+1scheme (2, 3, 4, and 11–14 months of age) to a 2+1scheme (2, 4, and 11–14 months of age). For premature infants, the 3+1scheme remained. The aim of this study was to assess vaccination rates, completeness, and timeliness for PCV in premature infants before and after the modified recommendation. MethodsA retrospective claims data analysis using the “Institut für angewandte Gesundheitsforschung Berlin” Research Database was conducted. Premature infants born in 2013 and 2016 with an individual follow-up of 24 months were included. Hexavalent combination (HEXA) vaccination with a consistent 3+1recommendation for mature and premature infants was analyzed as reference vaccination. ResultsAfter 24 months, the PCV rate for at least one dose remained stable in premature newborns of 2016 compared to 2013, while the HEXA vaccination rate increased slightly. However, a significant decrease of a completed PCV schedule (4 doses) in premature infants was noted, whereas the completeness of HEXA vaccination did not change. The timeliness of PCV in premature newborns increased for the first and the booster PCV, while the timeliness of HEXA immunization did not change from 2013 to 2016. ConclusionAlthough STIKO still recommends a 3+1PCV schedule for premature infants in Germany, premature infants were vaccinated according to the changed recommendations for mature born infants. A substantial share of premature infants remained unvaccinated, and their vaccinations were often delayed.

Index for the appropriate vancomycin dosing in premature neonates and infants.

BackgroundIn neonates, vancomycin (VCM) is used to treat Gram‐positive bacterial infections. However, VCM blood concentrations are affected by gestational age, bodyweight (BW), and renal function. The initial VCM dose adjustment can therefore be difficult, and few reports have evaluated this issue. In this study, we investigated the factors determining the appropriate VCM dosing schedule in neonates, especially premature infants.MethodsThe VCM dosage and trough concentrations were retrospectively investigated from the initial treatment to maintenance therapy in neonatal intensive care unit patients who underwent therapeutic drug monitoring. We examined the average single‐administration VCM dosage during maintenance therapy. We then compared the actual VCM dose with that calculated using an index comprising six items that influence the VCM daily dose (postnatal age, gestational age, BW, serum creatinine level, urine output, and lactate level).ResultsTwenty premature infants were included. The average BW of patients at the initial VCM administration was 975 g. During maintenance therapy, the average VCM dose was 8.4 mg/kg, and the median trough concentration was 12.4 μg/mL. When we applied the six‐item index, 18 of 20 patients (90%) had concordant results between the actual VCM dosing schedule and the VCM calculated using the index.ConclusionsThe average VCM dose and six‐item index can facilitate the transition from the initial VCM dose to an appropriate dose in many cases and contribute to early treatment in low‐birthweight infants with more variable BW, distribution volumes, and renal function. In conclusion, our six‐item index may help standardize VCM administration in premature infants.

Postnatal administration of systemic steroids increases severity of retinopathy in premature infants

Postnatal systemic steroids are known to increase the risk of developing retinopathy of prematurity (ROP). However, whether the total dosage and type of postnatal systemic steroids are related to the development and severity of ROP in premature infants remains unclear. This study was conducted to identify the risk factors for ROP and investigate the relationship between photocoagulation (PC)-demanding severe ROP and the postnatal dosage of any type of systemic steroids. A total of 75 infants born at <28 weeks of postmenstrual age (PMA) were enrolled. The number of PC procedures for ROP was evaluated as the objective variable. This study analyzed the following independent variables: gestational age; birth weight; sex; Apgar scores; duration of mechanical ventilation; duration of nasal intermittent positive pressure ventilation; mean saturation and mean oxygen concentration administration until 36 weeks of PMA; total accumulation dosage of hydrocortisone, dexamethasone, and systemic steroids; dosage number of times of erythropoietin; total dosage of red cell concentrates (RCC); incidence of necrotizing enterocolitis (NEC) and focal intestinal perforation; sepsis; bronchopulmonary dysplasia (BPD); and intraventricular hemorrhage (IVH). Logistic regression was used to estimate the relative risk (odds ratio (OR)) associated with risk factors for PC-demanding severe ROP. Compared with infants in the non-PC group, PC-treated infants had younger gestational age, longer mechanical ventilation periods, and higher dosage of systemic steroids and dexamethasone. Multivariate logistic regression analysis revealed total dosage of systemic steroids as the only risk factor for PC-demanding severe ROP. Based on receiver operating characteristic (ROC) curve analysis, a cutoff value of 8.95mg/kg of postnatal systemic steroid administration was identified as a useful marker to predict PC-demanding severe ROP. By focusing on the method of systemic steroid administration and avoiding excessive doses for infants born at <28 weeks of PMA, preventing the development of severe ROP is possible.

Antihistamine use during breastfeeding with focus on breast milk transfer and safety in humans: A systematic literature review.

Current data on use of antihistamines during breastfeeding and risks to the breastfed infant are insufficient. The aim of this systematic review was to provide an overview of studies measuring the levels of antihistamines in human breast milk, estimating the exposure for breastfed infants and/or reporting possible adverse effects on the breastfed infant. An additional aim was to review the antihistamine product labels available in the European Union (EU) and the United States. We searched seven online databases and identified seven human lactation studies that included 25 mother-infant pairs covering cetirizine, clemastine, ebastine, epinastine, loratadine, terfenadine and triprolidine. In addition, one study investigated the impact of chlorpheniramine or promethazine on prolactin levels among 17 women, and one study investigated possible adverse drug reactions in 85 breastfed infants exposed to various antihistamines. The relative infant dose was below 5% for all antihistamines, ranging from 0.3% for terfenadine to 4.5% for clemastine. Most product labels of the 10 antihistamines with available information in both the EU and the United States reported lack of evidence and recommended to avoid use during breastfeeding. The knowledge gap on antihistamines and lactation is extensive, and further human studies are warranted to ensure optimal treatment of breastfeeding women with allergy.

Comparing Vancomycin Area Under the Curve With a Pharmacist Protocol that Incorporates Trough and Maximum Doses at a Children's Hospital.

Updated vancomycin guidelines suggest dose adjustment based on area under the curve in a 24-hour period (AUC24). This study aims to determine whether a pharmacist managed vancomycin protocol that incorporates maximum dosing paired with trough monitoring can achieve appropriate vancomycin AUC24 exposures. A retrospective review was performed evaluating vancomycin usage from October 2018 through September 2019 at a children's hospital. Patients with less than 4 doses or lack a trough concentration were excluded. Vancomycin AUC24 were estimated using 2 calculations: 1) the Le method, incorporating age and serum creatinine, and 2) the trapezoidal method based upon population data and patient-specific trough. Target AUC24 ranges were assessed. AUC24 goals were 400 to 600 mg·hr/L, but due to known variations between calculations, a variance of 20 mg·hr/L was allowed for each end of the goal. Secondary analyses included evaluations of efficacy and toxicity. Two-hundred twenty-three patients were included. Initial doses were estimated to meet AUC24 goals in only 63%. After trough-based dose modification, 81% achieved a therapeutic AUC24. Using the trapezoidal method, therapeutic concentrations were found in 51% of patients based on the initial dose and 77% after dose modification. Only 6.3% of patients had kidney injury with only 1 of those patients having any calculated AUC24 > 600 mg·hr/L and none above 620 mg·hr/L. No clinical failures were identified. Increased initial dosing in infants and children is needed to result in AUC24 exposures recommended in the guidelines. Maximum dosing paired with trough monitoring may be an alternative to AUC24 monitoring in areas that are unable to perform AUC24 calculations. Prospective data are needed to validate these conclusions.

Initiation of Gender-Affirming Testosterone Therapy in a Lactating Transgender Man.

Transgender and gender diverse individuals may choose to provide their infants with human milk. Lactating transgender men may experience gender dysphoria and desire to initiate or reinitiate gender-affirming testosterone therapy. However, there is limited safety data regarding use of testosterone during lactation. A 30-year-old G2P2 transgender man with gender dysphoria sought to initiate gender-affirming testosterone therapy while lactating. Subcutaneous testosterone was self-administered beginning at 13 months post-partum. We prospectively collected data on circulating testosterone concentrations in parent serum, milk, and infant serum over 5 months until the infant self-weaned. The infant was monitored for growth and development at routine pediatric outpatient appointments. Parent serum testosterone concentrations rose with the initiation of testosterone therapy, reaching therapeutic concentrations by Day 14. Milk testosterone concentrations also increased with a maximum concentration of 35.9 ng/dl when the lactating parent was on a dose of 80 mg subcutaneous testosterone cypionate weekly. The calculated milk/plasma ratio remained under 1.0 and the calculated relative infant dose remained under 1%. The infant had no observable side effects, and his serum testosterone concentrations remained undetectable throughout the study period. This is the first study with data regarding human milk and infant serum testosterone concentrations during the initiation of gender-affirming testosterone therapy in a lactating individual. This evidence can help families and clinicians with decisions regarding lactation and testosterone use.

Drug and Neurofilament Levels in Serum and Breastmilk of Women With Multiple Sclerosis Exposed to Natalizumab During Pregnancy and Lactation.

ObjectiveTo determine the transfer of the monoclonal antibody natalizumab into breastmilk and to evaluate drug and serum neurofilament light chain ((s)NfL) levels in natalizumab exposed pregnancies and lactation periods.MethodsEleven women with relapsing remitting multiple sclerosis treated with natalizumab during pregnancy and lactation were included in this study. Breastmilk samples were collected up to 302 days after delivery and analyzed for natalizumab concentration and NfL. Additionally, maternal drug levels and sNfL were determined preconceptually, in each trimester, at delivery and postpartum. Clinical and radiological disease activity was systemically assessed across pregnancy and postpartum period.ResultsThe mean average natalizumab concentration in breast milk was low at 0.06 µg/ml [standard deviation (SD) 0.05] in the eight patients who provided serial breastmilk samples with an estimated mean absolute infant dose of 0.007 mg/kg/d (SD 0.005). The relative infant dose (RID), a metric comparing the infant with maternal drug exposure was low as well with a mean of 0.04% (SD=0.03). Most patients had a maximum concentration in breast milk at one to eight days after infusion. Pregnancy was associated with a non-significant decline of the median natalizumab serum concentration. All patients exposed to natalizumab prior (n=10) and during pregnancy (n=11) kept free of disease activity during gestation. While pregnancy was associated with low sNfL levels in patients treated with natalizumab prior and during pregnancy, the postpartum period was linked to a transient sNfL increase in some patients without any evidence of clinical or radiological disease activity. NfL was detectable in the majority of breastmilk samples with a median concentration of 1.7 pg/ml (range 0.004-18.1).ConclusionWe determined transfer of natalizumab into breastmilk with an RID far below the threshold of concern of 10%. Studies including childhood development assessment are needed in order to gain safety data about natalizumab-exposed breastfeeding. SNfL assessment might be a useful adjunct to monitor silent disease activity and therapeutic response during pregnancy and postpartum period. However, further investigations regarding transient postpartum sNfL increases are required to determine its association to parturition per se or to a silent disease activity in people with multiple sclerosis.