Sertraline, citalopram and paroxetine in lactation: passage into breastmilk and infant exposure.

Objectives: This study aimed to investigate the plasma and breastmilk concentrations for sertraline, citalopram and paroxetine for assessment of the Milk/Plasma (M/P) ratio and Absolute Infant Dose (AID), and to determine actual infant drug exposure through breastfeeding. Subsequently, informed recommendations will be formulated regarding the advisability of breastfeeding in women undergoing treatment with the three most widely used antidepressants. Methods: A pharmacokinetic study in lactating women and their infants using sertraline, citalopram or paroxetine was performed. Paired breastmilk and plasma samples and single point infant plasma samples were collected to determine antidepressant concentrations. An Area Under the Curve (AUC) based approach with the trapezoidal rule was used to calculate M/P ratios and AID for all three antidepressants by combining all measured concentrations for the same dose. Results: Thirty-seven lactating women and their infants participated in this study. 111 paired breastmilk and plasma samples and 37 single point infant plasma samples were collected. Detectable concentrations of sertraline, citalopram and paroxetine were present in all breastmilk samples. For sertraline and citalopram M/P ratio is above one, indicating higher breastmilk than plasma concentrations, however, drug exposure by breastmilk did not lead to detectable plasma drug levels in any of the 15 infants for sertraline, for nine (out of 13) infants for citalopram and for eight (out of nine) infants for paroxetine. Conclusion: Given the well-known benefits of breastfeeding, our findings support breastfeeding of infants by mothers who are taking sertraline, citalopram or paroxetine is safe. Sertraline and paroxetine are the preferred antidepressants during breastfeeding, reaching mostly undetectable infant drug levels.

Multipotent adult progenitor cells prevent functional impairment and improve development in inflammation driven detriment of preterm ovine lungs.

Background: Perinatal inflammation increases the risk for bronchopulmonary dysplasia in preterm neonates, but the underlying pathophysiological mechanisms remain largely unknown. Given their anti-inflammatory and regenerative capacity, multipotent adult progenitor cells (MAPC) are a promising cell-based therapy to prevent and/or treat the negative pulmonary consequences of perinatal inflammation in the preterm neonate. Therefore, the pathophysiology underlying adverse preterm lung outcomes following perinatal inflammation and pulmonary benefits of MAPC treatment at the interface of prenatal inflammatory and postnatal ventilation exposures were elucidated. Methods: Instrumented ovine fetuses were exposed to intra-amniotic lipopolysaccharide (LPS 5 mg) at 125 days gestation to induce adverse systemic and peripheral organ outcomes. MAPC (10 × 106 cells) or saline were administered intravenously two days post LPS exposure. Fetuses were delivered preterm five days post MAPC treatment and either killed humanely immediately or mechanically ventilated for 72 h. Results: Antenatal LPS exposure resulted in inflammation and decreased alveolar maturation in the preterm lung. Additionally, LPS-exposed ventilated lambs showed continued pulmonary inflammation and cell junction loss accompanied by pulmonary edema, ultimately resulting in higher oxygen demand. MAPC therapy modulated lung inflammation, prevented loss of epithelial and endothelial barriers and improved lung maturation in utero. These MAPC-driven improvements remained evident postnatally, and prevented concomitant pulmonary edema and functional loss. Conclusion: In conclusion, prenatal inflammation sensitizes the underdeveloped preterm lung to subsequent postnatal inflammation, resulting in injury, disturbed development and functional impairment. MAPC therapy partially prevents these changes and is therefore a promising approach for preterm infants to prevent adverse pulmonary outcomes.

Placental Pathology Contributes to Impaired Volumetric Brain Development in Neonates With Congenital Heart Disease.

BACKGROUND: Neonates with congenital heart disease are at risk for impaired brain development in utero, predisposing children to postnatal brain injury and adverse long-term neurodevelopmental outcomes. Given the vital role of the placenta in fetal growth, we assessed the incidence of placental pathology in fetal congenital heart disease and explored its association with total and regional brain volumes, gyrification, and brain injury after birth. METHODS AND RESULTS: Placentas from 96 term singleton pregnancies with severe fetal congenital heart disease were prospectively analyzed for macroscopic and microscopic pathology. We applied a placental pathology severity score to relate placental abnormalities to neurological outcome. Postnatal, presurgical magnetic resonance imaging was used to analyze brain volumes, gyrification, and brain injuries. Placental analyses revealed the following abnormalities: maternal vascular malperfusion lesions in 46%, nucleated red blood cells in 37%, chronic inflammatory lesions in 35%, delayed maturation in 30%, and placental weight below the 10th percentile in 28%. Severity of placental pathology was negatively correlated with cortical gray matter, deep gray matter, brainstem, cerebellar, and total brain volumes (r=-0.25 to -0.31, all P<0.05). When correcting for postmenstrual age at magnetic resonance imaging in linear regression, this association remained significant for cortical gray matter, cerebellar, and total brain volume (adjusted R2=0.25-0.47, all P<0.05). CONCLUSIONS: Placental pathology occurs frequently in neonates with severe congenital heart disease and may contribute to impaired brain development, indicated by the association between placental pathology severity and reductions in postnatal cortical, cerebellar, and total brain volumes.

First-trimester 3D power Doppler imaging markers of utero-placental vascular development are associated with placental weight and diameter at birth: The Rotterdam Periconception Cohort.

INTRODUCTION: Early utero-placental vascular development impacts placental development and function throughout pregnancy. We investigated whether impaired first-trimester utero-placental vascular development is associated with pathologic features of the postpartum placenta. METHODS: In this prospective observational study of 65 ongoing pregnancies, we obtained three-dimensional power Doppler ultrasounds of the placenta at 7, 9 and 11 weeks of gestation. We applied VOCAL software to measure placental volume (PV), virtual reality based segmentation to measure utero-placental vascular volume (uPVV) and applied a skeletonization algorithm to generate the utero-placental vascular skeleton (uPVS). Vascular morphology was quantified by assigning a morphologic characteristic to each voxel in the uPVS (i.e. end-, bifurcation-, crossing- or vessel point). Following delivery, placentas were measured and histologically examined according to the Amsterdam criteria to assess maternal vascular malperfusion (MVM). We used linear mixed models to estimate trajectories of PV, uPVV and uPVS development. Multivariable linear regression analysis with adjustments for confounders was used to evaluate associations between PV, uPVV and uPVS development and features of the postpartum placenta. RESULTS: We observed no associations between first-trimester PV development and measurements of the postpartum placenta. Increased first-trimester utero-placental vascular development, reflected by uPVV (ß = 0.25 [0.01; 0.48]), uPVS end points (ß = 0.25 [0.01; 0.48]), bifurcation points (ß = 0.22 [0.05; 0.37]), crossing points (ß = 0.29 [0.07; 0.52]) and vessel points (ß = 0.09 [0.02; 0.17]) was positively associated with the postpartum placental diameter. uPVV was positively associated with postpartum placental weight. No associations were found with MVM. DISCUSSION: Development of the first-trimester utero-placental vasculature is associated with postpartum placental size, whereas placental tissue development contributes to a lesser extent.

Anidulafungin Levels in Breast Milk After Cessation of Treatment: A Case Report.

Background: Anidulafungin has poor oral bioavailability, with hardly any available information on how it affects breast milk, oral absorption, or gastrointestinal side effects in the infant. Case Presentation: A 40-year-old woman who recently gave birth to a healthy infant was treated for a period of 14 days for a Candida glabrata with 100 mg anidulafungin once a day. The department of clinical pharmacy was consulted to provide advice on how long the patient had to wait after ceasing anidulafungin before it was safe to start breastfeeding, with regard to preventing possible side effects of the drug to the infant, such as diarrhea or cholestasis and increase in liver enzyme values. The advice of the hospital pharmacist was pragmatic: to start breastfeeding within 2 days after the medication was discontinued based on half-time. Results: Owing to this lack of information, we measured anidulafungin concentrations in breast milk and found low levels. Conclusion: We concluded that anidulafungin is detectable in breast milk until 32 hours after anidulafungin treatment was stopped, and that no side effects were observed by the infant.

Risks associated with antidepressants in patients with hypertension during pregnancy: a retrospective cohort study.

PURPOSE: In a cohort of pregnant women using antihypertensive drugs, we compared exposure to antidepressants versus no exposure and the possible association with birth weight, APGAR scores, NICU admission, and maternal admission to an obstetrical intensive care unit (OHC). It was hypothesized that pregnant women with hypertensive disorders using antidepressants are at greater risk of complications. METHODS: A retrospective cohort study in a general teaching hospital in Zwolle, in the Middle-Northern part of The Netherlands. Finally, 58 pregnancies in the exposed group and 273 pregnancies in the reference group met all inclusion and exclusion criteria. We compared the neonate's birthweight between the exposed to antidepressants group and the reference group as the primary outcome. Secondary outcomes were the APGAR score at 1 and 5 min and obstetric high care (OHC) admission of the mother and neonatal intensive care unit (NICU) admission of the child. RESULTS: We found no differences in birth weight in neonates of mothers with hypertensive disorders and whether or not to use antidepressants. Besides a possible higher risk of admission to an OHC in women with hypertension-complicated pregnancies using antidepressants, we found no other maternal or neonatal risks in this population. CONCLUSION: We found no additional maternal or neonatal risks of using antidepressants prescribed to women with hypertension disorders during pregnancy.

The Radiological and Histological Phenotype of Skeletal Abnormalities in Fetal ARCN1-Related Syndrome.

Mutations in ARCN1 give rise to a syndromic disorder with rhizomelic short stature with microretrognathia and developmental delay. ARCN1 encodes the delta subunit of the coat protein I complex, which is required for intracellular trafficking of collagen 1 and which may also be involved in the endoplasmic reticulum (ER) stress response. In this paper we describe for the first time the skeletal histological abnormalities in an 18-week-old fetus with an ARCN1 mutation, and we suggest that the skeletal phenotype in ARCN1-related syndrome has more resemblance with ER stress than with a defect in collagen 1 metabolism.

Asymptomatic Infant Rib Fractures Are Primarily Non-abuse-Related and Should Not Be Used to Assess Physical Child Abuse.

Finding infant rib fractures was for many years an almost undisputed proof that physical child abuse took place. Yet, these rib fractures are virtually always occult and asymptomatic and are only identified when looked for, usually with X-rays, from physical child abuse accusations related to, e.g., suspicion of the shaken baby syndrome. In a recent systematic literature review (searched in Cochran, Embase, PubMed and Sociological Abstracts), Güvensel questioned the diagnostic accuracy of rib fractures to be caused by abuse, due to lack of sufficient scientific evidence. Further, there is currently a world-wide disagreement between physicians considering themselves child abuse specialized, and physicians that explore non-abuse-related symptoms that may mimic physical abuse, which, it is hoped, will significantly reduce current unjustified child abuse diagnoses. In an attempt to help resolving this disagreement, we hypothesize that the probability of physical child abuse-related infant rib fractures is significantly lower than the probability of all other possible non-abuse-related causes of occult asymptomatic infant rib fractures, e.g., from birth trauma, prematurity, osteogenesis imperfecta, hypermobile Ehlers-Danlos Syndrome, severe chronic placental pathology (e.g., massive perivillous fibrin depositions and severe chronic histiocytic intervillositis), and vitamin-D deficiency. As method, we attempted to assess the incidence of these various causes of infant rib fractures, in the Netherlands and the USA. The results are that the estimated Dutch and USA physical abuse-related infant rib fracture incidences are at least about 250 and 45 times lower than the sum of all the non-abuse-related estimates. Because these latter rib fractures are occult and asymptomatic, it is likely that (many) more could be out there. In conclusion, occult asymptomatic rib fractures develop perinatally, virtually always as birth trauma, in infants with sufficiently weak bones due to vitamin D deficiency, transmitted by their vitamin D deficient pregnant mothers. This group also includes cortical rib cracks due to deformation forces, with an estimated 186/100,000 incidence. And, despite obvious uncertainties in all estimated incidences, we provided strong evidence that our hypothesis has relevance, implying that the abundant occult asymptomatic rib fractures, when found in infants, should not be used to assess potential physical child abuse.

Maturation and Function of the Intercalated Disc: Report of Two Pediatric Cases Focusing on Cardiac Development and Myocardial Hyperplasia.

The development of the normal human heart, ranging from gestational age to the mature adult heart, relies on a very delicate and timely orchestrated order of processes. One of the most striking alterations in time is the gradual extinction of the ability for cardiomyocytes to proliferate. Once passing this event, cardiomyocytes grow and increase in contractile strength by means of physiological hypertrophy. This process, importantly, seems to depend on an adequate development of electromechanical coupling that is achieved by the appropriate formation of the intercellular junction named the intercalated disc (ICD). In this report, we describe two sudden death cases of young and apparently healthy-born individuals without external abnormalities compared to an age-matched control. Histological examination, including the comparison with the age-matched and histology-matched controls, showed a disturbed formation of the protein machinery composing the electromechanical junctions at the ICD and an increased nuclei count for both patients. As a cause or consequence, cardiomyocytes in both sudden death cases showed signs of a delayed developmental stage, presumably resulting in an exaggerated degree of hyperplasia.

Chronic airflow obstruction attributable to poverty in the multinational Burden of Obstructive Lung Disease (BOLD) study.

Poverty is strongly associated with all-cause and chronic obstructive pulmonary disease (COPD) mortality. Less is known about the contribution of poverty to spirometrically defined chronic airflow obstruction (CAO)-a key characteristic of COPD. Using cross-sectional data from an asset-based questionnaire to define poverty in 21 sites of the Burden of Obstructive Lung Disease study, we estimated the risk of CAO attributable to poverty. Up to 6% of the population over 40 years had CAO attributable to poverty. Understanding the relationship between poverty and CAO might suggest ways to improve lung health, especially in low-income and middle-income countries.

Identification of a unique intervillous cellular signature in chronic histiocytic intervillositis.

INTRODUCTION: Chronic histiocytic intervillositis (CHI) is a rare histopathological lesion in the placenta characterized by an infiltrate of CD68+ cells in the intervillous space. CHI is associated with adverse pregnancy outcomes such as miscarriage, fetal growth restriction, and (late) intrauterine fetal death. The adverse pregnancy outcomes and a variable recurrence rate of 25-100% underline its clinical relevance. The pathophysiologic mechanism of CHI is unclear, but it appears to be immunologically driven. The aim of this study was to obtain a better understanding of the phenotype of the cellular infiltrate in CHI. METHOD: We used imaging mass cytometry to achieve in-depth visualization of the intervillous maternal immune cells and investigated their spatial orientation in situ in relation to the fetal syncytiotrophoblast. RESULTS: We found three phenotypically distinct CD68+HLA-DR+CD38+ cell clusters that were unique for CHI. Additionally, syncytiotrophoblast cells in the vicinity of these CD68+HLA-DR+CD38+ cells showed decreased expression of the immunosuppressive enzyme CD39. DISCUSSION: The current results provide novel insight into the phenotype of CD68+ cells in CHI. The identification of unique CD68+ cell clusters will allow more detailed analysis of their function and could result in novel therapeutic targets for CHI.

Maternal and neonatal outcomes after benzodiazepine and benzodiazepine agonist exposure during pregnancy in women with mental disorders.

AIMS: To compare the gestational age of neonates in utero exposed to benzodiazepines (BDZs) with nonexposed controls. Secondary objectives were birth weight, presence of congenital malformations, APGAR score and the need for >3 months (prolonged) maternal psychiatric care. METHODS: A retrospective cohort study of women and neonates from 2013 to 2021 with univariate and multivariable analysis to study the associations between BDZ exposure and gestational age compared to nonexposed women with mental health problems. RESULTS: We found that BDZ exposure was not associated with a lower gestational age. We found that women in the exposed group had an increased risk of psychiatric care (adjusted odds ratio 2.58 [95% confidence interval 1.71-3.91], P < .001). CONCLUSION: We found that in utero BDZ exposure was not associated with a significantly lower gestational age of the neonates and was associated with prolonged psychiatric care of their mothers.

Analytical and clinical validation of an LC-MS/MS method for carbamazepine, lamotrigine and levetiracetam in dried blood spots.

OBJECTIVES: Therapeutic drug monitoring is performed routinely in patients on anti-epileptic drugs (AEDs) for optimisation and individualisation of therapy. The dried blood spot (DBS) sampling technique is a suitable, more patient-friendly alternative for conventional venous sampling methods. However, before DBS can be used in routine care, data are needed to establish the correlation between standard plasma concentrations obtained from venous puncture and concentrations measured through DBS obtained by finger prick. This study aims to investigate the correlation between carbamazepine, lamotrigine and levetiracetam drug concentrations in venous blood and DBS samples in the same patients at the same time. METHODS: Clinical validation was conducted by direct comparison of paired DBS and venous plasma samples. Method agreement was evaluated using Passing-Bablok regression analysis and Bland-Altman plots to provide insight into the relationship between the two analytically validated methods. For Bland-Altman analysis the acceptance limit required by both FDA and EMA guidelines is at least two-thirds (67%) of the paired samples within 80-120% of the mean of both methods. RESULTS: Paired samples from 79 patients were studied. For all three AEDs, plasma and DBS concentrations correlated highly (r=0.90 for carbamazepine, r=0.93 for lamotrigine and r=0.93 for levetiracetam), indicating a linear relationship. For carbamazepine and lamotrigine, no proportional or constant bias was revealed. For levetiracetam, concentrations were higher in plasma samples than in DBS (slope 1.21), implying a conversion factor is needed. The acceptance limit was met for carbamazepine and levetiracetam with a value of 72% and 81%, respectively. For lamotrigine, this acceptance limit was not met with a value of 60%. CONCLUSIONS: The method was successfully validated and will be used for therapeutic drug monitoring in patients using carbamazepine, lamotrigine and/or levetiracetam.

Target attainment and pharmacokinetics of cefotaxime in critically ill patients undergoing continuous kidney replacement therapy.

OBJECTIVES: Limited data exist about the antimicrobial target attainment and pharmacokinetics of cefotaxime in critically ill patients in the ICU undergoing continuous kidney replacement therapy (CKRT). We conducted a prospective observational study in two large teaching hospitals [Isala Hospital (IH) and Zwolle and Maasstad Hospital (MH)] to investigate target attainment and pharmacokinetics of cefotaxime in patients undergoing CKRT. PATIENTS AND METHODS: Patients aged ≥18 years admitted to the ICU treated with IV cefotaxime 1000 mg three times daily (IH) or 4 times daily (MH) were included. Fifteen patients were enrolled in total. Per patient eight cefotaxime plasma and eight ultrafiltrate samples were drawn in IH and four plasma samples in MH on Day 2 of treatment. In ICU patients the recommended antimicrobial target of cefotaxime is a plasma concentration 100% of the time above the MIC. RESULTS: In IH 10/11 patients had higher plasma trough concentrations than the MIC breakpoint of Enterobacterales of 1 mg/L (clinical breakpoint for susceptible strains) and 9/11 patients had concentrations above 2 mg/L (clinical breakpoint for resistant strains). All patients (4/4) in MH had higher plasma trough concentrations than 2 mg/L. A sieving coefficient of 0.74 was identified, with a median amount of 40% of cefotaxime eliminated by CKRT. CONCLUSIONS: We conclude that cefotaxime 1000 mg 3-4 times daily gives adequate plasma concentrations in patients with anuria or oliguria undergoing CKRT. The 1000 mg four times daily dosage is recommended in patients undergoing CKRT with partially preserved renal function to achieve the target.

Cognitive Impairments in Patients with GHB Use Disorder Predict Relapse in GHB Use.

BACKGROUND: The recreational use of gamma hydroxybutyrate (GHB) is associated with frequent overdoses, coma and the risk of developing GHB use disorder (GUD). Several studies suggest negative effects of GHB use or related comas on cognition. Since relapse rates are high in GUD and cognitive impairment has been associated with relapse in other substance use disorders, we aimed to (1) investigate the prevalence of cognitive impairment before and after detoxification, (2) analyse the relationship between GHB use, comas, and cognitive impairment, and (3) explore the association between cognitive impairment and relapse after detoxification in GUD patients. METHODS: In these secondary analyses of a prospective cohort study, a consecutive series of patients with GUD (n = 103) admitted for detoxification were recruited at six addiction care facilities in the Netherlands. The Montreal Cognitive Assessment (MoCA) was used to screen for cognitive impairments before and after detoxification. The follow-up duration for the assessment of relapse in GHB use was 3 months. RESULTS: A substantial number of patients with GUD screened positive for cognitive impairment before (56.3%) and after (30.6%) detoxification. Impairment on the MoCA memory domain was most frequent (58.8%). Cognitive impairment was not related to the severity of GUD or number of GHB-induced comas. Logistic regression analysis showed that only the memory score independently predicted relapse. DISCUSSION: Cognitive impairment seems highly prevalent among patients with GUD, possibly related to the risk of relapse. The absence of a relationship between the severity of GUD, level of GHB use, the number of GHB-induced comas, and cognitive impairment suggest that other factors may also contribute to the observed cognitive impairment.

Clinical and Molecular Diagnosis of Osteocraniostenosis in Fetuses and Newborns: Prenatal Ultrasound, Clinical, Radiological and Pathological Features.

Osteocraniostenosis (OCS, OMIM #602361) is a severe, usually lethal condition characterized by gracile bones with thin diaphyses, a cloverleaf-shaped skull and splenic hypo/aplasia. The condition is caused by heterozygous mutations in the FAM111A gene and is allelic to the non-lethal, dominant disorder Kenny-Caffey syndrome (KCS, OMIM #127000). Here we report two new cases of OCS, including one with a detailed pathological examination. We review the main diagnostic signs of OCS both before and after birth based on our observations and on the literature. We then review the current knowledge on the mutational spectrum of FAM111A associated with either OCS or KCS, including three novel variants, both from one of the OCS fetuses described here, and from further cases diagnosed at our centers. This report refines the previous knowledge on OCS and expands the mutational spectrum that results in either OCS or KCS.

Restricted spirometry and cardiometabolic comorbidities: results from the international population based BOLD study.

BACKGROUND: Whether restricted spirometry, i.e. low Forced Vital Capacity (FVC), predicts chronic cardiometabolic disease is not definitely known. In this international population-based study, we assessed the relationship between restricted spirometry and cardiometabolic comorbidities. METHODS: A total of 23,623 subjects (47.5% males, 19.0% current smokers, age: 55.1 ± 10.8 years) from five continents (33 sites in 29 countries) participating in the Burden of Obstructive Lung Disease (BOLD) study were included. Restricted spirometry was defined as post-bronchodilator FVC < 5th percentile of reference values. Self-reports of physician-diagnosed cardiovascular disease (CVD; heart disease or stroke), hypertension, and diabetes were obtained through questionnaires. RESULTS: Overall 31.7% of participants had restricted spirometry. However, prevalence of restricted spirometry varied approximately ten-fold, and was lowest (8.5%) in Vancouver (Canada) and highest in Sri Lanka (81.3%). Crude odds ratios for the association with restricted spirometry were 1.60 (95% CI 1.37-1.86) for CVD, 1.53 (95% CI 1.40-1.66) for hypertension, and 1.98 (95% CI 1.71-2.29) for diabetes. After adjustment for age, sex, education, Body Mass Index (BMI) and smoking, the odds ratios were 1.54 (95% CI 1.33-1.79) for CVD, 1.50 (95% CI 1.39-1.63) for hypertension, and 1.86 (95% CI 1.59-2.17) for diabetes. CONCLUSION: In this population-based, international, multi-site study, restricted spirometry associates with cardiometabolic diseases. The magnitude of these associations appears unattenuated when cardiometabolic risk factors are taken into account.