No Measurable Transfer of Oxytocin-Receptor Agonist Merotocin Detected in Human Breast Milk.

Objective: The study aimed to assess the transfer of merotocin from systemic circulation to breast milk in early postpartum women and women with established lactation. Methods: This was a two-part, multicenter, open-label, parallel-group study. Merotocin was administered as a single 90-minute intravenous (iv) infusion mimicking the intranasal pharmacokinetic profile. In Part A, 12 early postpartum women received doses of either 4 µg (n = 6) or 16 µg (n = 6) of merotocin within 4 days of delivery. In Part B, six women with established lactation received 20 µg of merotocin. The total concentration of merotocin in plasma and breast milk and its metabolites excreted in breast milk were measured at various time points. Adverse events (AEs) were also assessed for both parts of the study. Results: In both early postpartum and established lactation groups (mean age, 26.3 years; 83.3% Caucasian), merotocin and its metabolites in breast milk were below the limit of quantification (25.0 pg/mL) at all time points. Sixteen treatment-emergent AEs occurred in early postpartum women only, including seven events of uterine spasm and three of breast engorgement. There was one moderate event, whereas all the other events were considered mild. Conclusion: Merotocin was undetectable in breast milk after single iv administration of up to 20 µg in early postpartum women and women with established lactation.

Anti-CD20 monoclonal antibody therapy in postpartum women with neurological conditions.

OBJECTIVE: Postpartum, patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) have increased risk for disease activity. Anti-CD20 IgG1 monoclonal antibodies (mAb) are increasingly used as disease-modifying therapies (DMTs). Patients may wish to both breastfeed and resume DMT postpartum. This study aimed to determine the transfer of anti-CD20 IgG1 mAbs, ocrelizumab, and rituximab (OCR/RTX), into mature breastmilk and describe maternal and infant outcomes. METHODS: Fifty-seven cis-women receiving OCR/RTX after 59 pregnancies and their infants were enrolled and followed up to 12M postpartum or 90 days post-infusion. Breastmilk was collected pre-infusion and serially up to 90 days and assayed for mAb concentration. Medical records and patients' questionnaire responses were obtained to assess neurologic, breastfeeding, and infant development outcomes. RESULTS: The median average concentration of mAb in breastmilk was low (OCR: 0.08 µg/mL, range 0.05-0.4; RTX: 0.03 µg/mL, range 0.005-0.3). Concentration peaked 1-7 days post-infusion in most (77%) and was nearly undetectable after 90 days. Median average relative infant dose was <1% (OCR: 0.1%, range 0.07-0.7; RTX: 0.04%, range 0.005-0.3). Forty-three participants continued to breastfeed post-infusion. At 8-12 months, the proportion of infants' growth between the 3rd and 97th World Health Organization percentiles did not differ for breastfed (36/40) and non-breastfed (14/16, p > 0.05) infants; neither did the proportion with normal development (breastfed: 37/41, non-breastfed: 11/13; p > 0.05). After postpartum infusion, two mothers experienced a clinical relapse. INTERPRETATION: These confirm minimal transfer of mAb into breastmilk. Anti-CD20 mAb therapy stabilizes MS activity before conception to the postpartum period, and postpartum treatments appears to be safe and well-tolerated for both mother and infant.

Pharmacokinetics of Ketamine Transfer Into Human Milk.

PURPOSE/BACKGROUND: Ketamine is an N -methyl- d -aspartate-antagonistic dissociative anesthetic infused intermittently for off-label management of treatment-resistant depression, acute suicidality, and postpartum depression. Despite the prevalence of postpartum depression nearing upward of 15% of deliveries, almost no research has been done to evaluate its safety during lactation. METHODS: In this study, human milk samples were released from the InfantRisk Center's Human Milk Biorepository of 4 participants treated with intermittent ketamine infusions (49-378 mg) to determine the levels of the drug and its active norketamine metabolite using liquid chromatography-mass spectrometry. RESULTS: The absolute infant dose of ketamine from human milk was 0.003 to 0.017 mg/kg per day, and norketamine was 0.005 to 0.018 mg/kg per day. The relative infant dose (RID) for ketamine ranged from 0.34% to 0.57%. The RID for norketamine ranged from 0.29% to 0.95%. There were no reported infant adverse effects. CONCLUSION: The findings of this study suggest that the transfer of ketamine, as well as its active metabolite, norketamine, into human milk is minimal, as estimated by RIDs less than 1% in all participants. These relative doses are well below standardly accepted safety thresholds.

A panel dataset of COVID-19 vaccination policies in 185 countries.

We present a panel dataset of COVID-19 vaccine policies, with data from 01 January 2020 for 185 countries and a number of subnational jurisdictions, reporting on vaccination prioritization plans, eligibility and availability, cost to the individual and mandatory vaccination policies. For each of these indicators, we recorded who is targeted by a policy using 52 standardized categories. These indicators document a detailed picture of the unprecedented scale of international COVID-19 vaccination rollout and strategy, indicating which countries prioritized and vaccinated which groups, when and in what order. We highlight key descriptive findings from these data to demonstrate uses for the data and to encourage researchers and policymakers in future research and vaccination planning. Numerous patterns and trends begin to emerge. For example: 'eliminator' countries (those that aimed to prevent virus entry into the country and community transmission) tended to prioritize border workers and economic sectors, while 'mitigator' countries (those that aimed to reduce the impact of community transmission) tended to prioritize the elderly and healthcare sectors for the first COVID-19 vaccinations; high-income countries published prioritization plans and began vaccinations earlier than low- and middle-income countries. Fifty-five countries were found to have implemented at least one policy of mandatory vaccination. We also demonstrate the value of combining this data with vaccination uptake rates, vaccine supply and demand data, and with further COVID-19 epidemiological data.

Trends in invasive bacterial diseases during the first 2 years of the COVID-19 pandemic: analyses of prospective surveillance data from 30 countries and territories in the IRIS Consortium.

BACKGROUND: The Invasive Respiratory Infection Surveillance (IRIS) Consortium was established to assess the impact of the COVID-19 pandemic on invasive diseases caused by Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, and Streptococcus agalactiae. We aimed to analyse the incidence and distribution of these diseases during the first 2 years of the COVID-19 pandemic compared to the 2 years preceding the pandemic. METHODS: For this prospective analysis, laboratories in 30 countries and territories representing five continents submitted surveillance data from Jan 1, 2018, to Jan 2, 2022, to private projects within databases in PubMLST. The impact of COVID-19 containment measures on the overall number of cases was analysed, and changes in disease distributions by patient age and serotype or group were examined. Interrupted time-series analyses were done to quantify the impact of pandemic response measures and their relaxation on disease rates, and autoregressive integrated moving average models were used to estimate effect sizes and forecast counterfactual trends by hemisphere. FINDINGS: Overall, 116 841 cases were analysed: 76 481 in 2018-19, before the pandemic, and 40 360 in 2020-21, during the pandemic. During the pandemic there was a significant reduction in the risk of disease caused by S pneumoniae (risk ratio 0·47; 95% CI 0·40-0·55), H influenzae (0·51; 0·40-0·66) and N meningitidis (0·26; 0·21-0·31), while no significant changes were observed for S agalactiae (1·02; 0·75-1·40), which is not transmitted via the respiratory route. No major changes in the distribution of cases were observed when stratified by patient age or serotype or group. An estimated 36 289 (95% prediction interval 17 145-55 434) cases of invasive bacterial disease were averted during the first 2 years of the pandemic among IRIS-participating countries and territories. INTERPRETATION: COVID-19 containment measures were associated with a sustained decrease in the incidence of invasive disease caused by S pneumoniae, H influenzae, and N meningitidis during the first 2 years of the pandemic, but cases began to increase in some countries towards the end of 2021 as pandemic restrictions were lifted. These IRIS data provide a better understanding of microbial transmission, will inform vaccine development and implementation, and can contribute to health-care service planning and provision of policies. FUNDING: Wellcome Trust, NIHR Oxford Biomedical Research Centre, Spanish Ministry of Science and Innovation, Korea Disease Control and Prevention Agency, Torsten Söderberg Foundation, Stockholm County Council, Swedish Research Council, German Federal Ministry of Health, Robert Koch Institute, Pfizer, Merck, and the Greek National Public Health Organization.

Transfer of Injected Triamcinolone into Human Milk of a Lactating Patient Suffering from Idiopathic Granulomatous Mastitis.

Background: Idiopathic granulomatous mastitis (IGM) is a chronic inflammatory condition of the mammary gland that presents as a painful mass, and it must be distinguished from both infectious mastitis and breast cancer. When diagnosed during lactation, it can result in significant distress and early weaning. Injection of triamcinolone has been used as a successful treatment method, but safety in breastfed infants has not been established. Methods: We present a case of a lactating patient who received a direct injection of triamcinolone (dosage 40 mg) in her breast to treat IGM after failure of oral corticosteroids. Breastmilk samples were expressed by the patient 0, 1, 4, and 24 hours after the procedure, and then daily for 1 week. All the samples were analyzed using liquid chromatography mass spectrometry. The patient was supported by a breastfeeding and lactation medicine clinic. Results: After injection of triamcinolone into the granulomatous mass, breast milk samples were collected and analyzed. No samples were found to contain triamcinolone. A temporary but significant decrease in milk production was noted after injection, though only a slight decrease had been noted with 6 weeks of systemic corticosteroids. With support, the patient rebuilt milk production and continued to breastfeed from both breasts. Conclusion: Triamcinolone was not found in any milk samples (≥0.78 ng/mL) following therapeutic injection of the affected breast. The patient was able to continue breastfeeding from the affected breast with intermittent symptoms.

Psychiatric Manifestations of Withdrawal Following Domperidone Used as a Galactagogue.

Background: Domperidone is a dopamine-2 antagonist used off-label to increase breast milk production. Dosages commonly promoted for lactation are often far above those of studied on-label indications and might pose additional risks, especially upon discontinuation of the drug. Patients: Three U.S. patients are presented who used domperidone for lactation and experienced varying degrees of psychiatric withdrawal symptoms lasting months during dosage tapering and after cessation. Conclusion: Domperidone as a galactagogue may pose a significant psychiatric risk upon discontinuation. This presentation is commonly confused with, but clinically distinct from, postpartum depression. Lactating mothers who present with psychiatric symptoms should be explicitly probed about domperidone use, even in areas where domperidone is not authorized for use. Maternal hesitancy to disclose domperidone use may lead to suboptimal outcomes for the patient and delay management of withdrawal manifestations. The best course of treatment remains unknown, but a slow hyperbolic taper to gently discontinue domperidone may minimize withdrawal symptoms in these patients. Individuals exploring domperidone use should be informed of potential risks upon withdrawal, including psychiatric manifestations, requisite taper, and potential impacts of using unstudied high doses.

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.

Pharmacokinetics of a single dose of oclacitinib maleate as a top dress in adult horses.

The objective of this study was to determine the pharmacokinetic parameters of oclacitinib maleate as a top dress given to adult horses. Six adult horses with a mean weight of 528 kg were administered a single dose of 0.5 mg/kg oclacitinib maleate. Blood was collected prior to drug administration and at 15 min, 30 min, 45 min, 1, 2, 4, 6, 8, 12, 24, 48, and 72 h after treatment. Oclacitinib maleate plasma concentrations were measured by liquid chromatography/mass spectrometry. Pharmacokinetic parameters were found best to fit a one-compartment model. Mean Cmax was 486 ng/ml (range 423-549 ng/ml), and Tmax was estimated to be 1.7 h (range 0.3-3.1 h). The estimated T1/2 was 7.5-8 h.

Mode of Cannabis Use and Factors Related to Frequency of Cannabis Use Among Breastfeeding Mothers: Results from an Online Survey.

Background: In the United States, 5% of breastfeeding mothers report using cannabis. Frequent cannabis use results in higher delta-9-tetrahydrocannabinol (THC) in breast milk, and mode of cannabis use may also impact risk to the infant. The aim of this study was to understand how breastfeeding mothers use cannabis and factors related to frequency of its use. Methods: An anonymous online survey was conducted among mothers who used cannabis while breastfeeding. Frequency of cannabis use was ascertained along with modes of and reasons for cannabis use. Respondents were grouped by frequency of use: less-than-daily (n = 686), low-daily (1-3 times/day; n = 423), and high-daily (≥4 times/day; n = 218). Chi-square and analysis of variance tested between-group differences, and ordinal logistic regression examined factors associated with cannabis use frequency. Results: Smoking (88%) was the most common mode of cannabis consumption, followed by vaping (48%) and oral/edibles (36%). Smoking and vaping differed by cannabis use frequency. Only 54% used cannabis to get high, but was reported more among frequent users. In contrast, 89% of mothers used cannabis for mental or physical health symptoms, including anxiety, depression, gastrointestinal symptoms, chronic pain, and posttraumatic stress disorder. These symptoms differed by cannabis use frequency. Reporting more symptoms was associated with higher frequency of use. The odds of increasing cannabis use frequency was 2.7 for those reporting 1-2 health reasons, 5.6 for those reporting 3-4 health reasons, and 13.1 for reporting ≥5 health reasons. Conclusions: Strategies are needed to address maternal mental and physical health, which may be key to reducing cannabis use among breastfeeding mothers.

A worldwide assessment of changes in adherence to COVID-19 protective behaviours and hypothesized pandemic fatigue.

As the COVID-19 pandemic lingers, the possibility of 'pandemic fatigue' has raised worldwide concerns. Here, we examine whether there was a gradual reduction in adherence to protective behaviours against COVID-19 from March through December 2020, as hypothesized in expectations of fatigue. We considered self-report behaviours from representative samples of the populations of 14 countries (N = 238,797), as well as mobility and policy data for 124 countries. Our results show that changes in adherence were empirically meaningful and geographically widespread. While a low-cost and habituating behaviour (mask wearing) exhibited a linear rise in adherence, high-cost and sensitizing behaviours (physical distancing) declined, but this decline decelerated over time, with small rebounds seen in later months. Reductions in adherence to physical distancing showed little difference across societal groups, but were less intense in countries with high interpersonal trust. Alternative underlying mechanisms and policy implications are discussed.

Human Milk Endocannabinoid Levels as a Function of Obesity and Diurnal Rhythm.

The endocannabinoid system is involved in the regulation of a variety of physiological and cognitive processes. While the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (N-arachidonoylethanolamine, AEA) have been found in breast milk, their role(s) have yet to be determined. This study determined the normal concentration ranges of endocannabinoids (2-AG and AEA) in breast milk and the influences, if any, of obesity and diurnal rhythms on their levels. Milk samples were collected from 36 breastfeeding mothers at 4-8 weeks postpartum at each feed over a 24-h period, and further stratified into three groups based on body mass index (BMI). The samples were analyzed using liquid chromatography mass spectrometry. AEA was below the limit of detection and 2-AG levels averaged 59.3 ± 18.3 ng/mL (± SD) in women with normal BMI. Wide-ranging 2-AG concentrations in the overweight (65.5 ± 41.9 ng/mL) /obese (66.1 ± 40.6 ng/mL) groups suggest BMI may be a contributing factor influencing its levels. Following a diurnal pattern, there was a significantly higher 2-AG concentration observed during the day, as compared to night time samples. In conclusion, our study clearly suggests that appropriate milk collection and storage conditions are critical. Further, body weight and diurnal rhythm appear to influence levels of 2-AG. Based on these results, future studies are underway to determine what specific roles endocannabinoids may play in human milk and how elevated levels of 2-AG may modulate infant appetite and health.

Government responses and COVID-19 deaths: Global evidence across multiple pandemic waves.

We provide an assessment of the impact of government closure and containment measures on deaths from COVID-19 across sequential waves of the COVID-19 pandemic globally. Daily data was collected on a range of containment and closure policies for 186 countries from January 1, 2020 until March 11th, 2021. These data were combined into an aggregate stringency index (SI) score for each country on each day (range: 0-100). Countries were divided into successive waves via a mathematical algorithm to identify peaks and troughs of disease. Within our period of analysis, 63 countries experienced at least one wave, 40 countries experienced two waves, and 10 countries saw three waves, as defined by our approach. Within each wave, regression was used to assess the relationship between the strength of government stringency and subsequent deaths related to COVID-19 with a number of controls for time and country-specific demographic, health system, and economic characteristics. Across the full period of our analysis and 113 countries, an increase of 10 points on the SI was linked to 6 percentage points (P < 0.001, 95% CI = [5%, 7%]) lower average daily deaths. In the first wave, in countries that ultimately experiences 3 waves of the pandemic to date, ten additional points on the SI resulted in lower average daily deaths by 21 percentage points (P < .001, 95% CI = [8%, 16%]). This effect was sustained in the third wave with reductions in deaths of 28 percentage points (P < .001, 95% CI = [13%, 21%]). Moreover, interaction effects show that government policies were effective in reducing deaths in all waves in all groups of countries. These findings highlight the enduring importance of non-pharmaceutical responses to COVID-19 over time.