Placental infection by Zika virus in French Guiana.

OBJECTIVES: To describe placental findings on prenatal ultrasound and anatomopathological examination in women with Zika virus (ZIKV) infection, and to assess their association with congenital ZIKV infection and severe adverse outcome, defined as fetal loss or congenital Zika syndrome (CZS). METHODS: This was a prospective study of pregnancies undergoing testing for maternal ZIKV infection at a center in French Guiana during the ZIKV epidemic. In ZIKV-positive women, congenital infection was defined as either a positive reverse transcription polymerase chain reaction result or identification of ZIKV-specific immunoglobulin-M in at least one placental, fetal or neonatal sample. Placental ZIKV-infection status was classified as non-exposed (placentae from non-infected women), exposed (placentae from ZIKV-infected women without congenital infection) or infected (placentae from ZIKV-infected women with proven congenital infection). Placentae were assessed by monthly prenatal ultrasound examinations, measuring placental thickness and umbilical artery Doppler parameters, and by anatomopathological examination after live birth or intrauterine death in women with ZIKV infection. The association of placental thickness during pregnancy and anatomopathological findings with the ZIKV status of the placenta was assessed. The association between placental findings and severe adverse outcome (CZS or fetal loss) in the infected group was also assessed. RESULTS: Among 291 fetuses/neonates/placentae from women with proven ZIKV infection, congenital infection was confirmed in 76 cases, of which 16 resulted in CZS and 11 resulted in fetal loss. The 215 remaining placentae from ZIKV-positive women without evidence of congenital ZIKV infection represented the exposed group. A total of 334 placentae from ZIKV-negative pregnant women represented the non-exposed control group. Placentomegaly (placental thickness > 40 mm) was observed more frequently in infected placentae (39.5%) than in exposed placentae (17.2%) or controls (7.2%), even when adjusting for gestational age at diagnosis and comorbidities (adjusted hazard ratio (aHR), 2.02 (95% CI, 1.22-3.36) and aHR, 3.23 (95% CI, 1.86-5.61), respectively), and appeared earlier in infected placentae. In the infected group, placentomegaly was observed more frequently in cases of CZS (62.5%) or fetal loss (45.5%) than in those with asymptomatic congenital infection (30.6%) (aHR, 5.43 (95% CI, 2.17-13.56) and aHR, 4.95 (95% CI, 1.65-14.83), respectively). Abnormal umbilical artery Doppler was observed more frequently in cases of congenital infection resulting in fetal loss than in those with asymptomatic congenital infection (30.0% vs 6.1%; adjusted relative risk (aRR), 4.83 (95% CI, 1.09-20.64)). Infected placentae also exhibited a higher risk for any pathological anomaly than did exposed placentae (62.8% vs 21.6%; aRR, 2.60 (95% CI, 1.40-4.83)). CONCLUSIONS: Early placentomegaly may represent the first sign of congenital infection in ZIKV-infected women, and should prompt enhanced follow-up of these pregnancies. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

[Antiepileptics in women of childbearing age and during pregnancy: comparison of specialized information with the current state of knowledge in Germany and Switzerland]. / Antiepileptika bei Frauen im gebärfähigen Alter und in der Schwangerschaft : Vergleich der Fachinformationen in Deutschland und der Schweiz mit dem aktuellen Wissensstand.

BACKGROUND: Healthcare professionals regularly read the summary of product characteristics (SmPC) as one of the various sources of information on the risks of drug use in women of childbearing age and during pregnancy. The aim of this article is to present an overview of the teratogenic potential of various antiepileptic drugs and to compare these data with the information provided by the SmPCs. METHODS: A literature search on the teratogenic risks of 19 antiepileptic agents was conducted and the results were compared with the information on the use in women of childbearing age and during pregnancy provided by the SmPCs of 38 commercial products available in Switzerland and Germany. RESULTS: The teratogenic risk is discussed in all available SmPCs. Quantification of the risk for birth defects and the numbers of documented pregnancies are mostly missing. Reproductive safety information in SmPCs showed poor concordance with risk levels reported in the literature. Recommendations concerning the need to monitor plasma levels and possibly perform dose adjustments during pregnancy to prevent treatment failure were missing in five Swiss and two German SmPCs. DISCUSSION: The information regarding use in women of childbearing age and during pregnancy provided by the SmPCs is heterogeneous and poorly reflects the current state of knowledge. Regular updates of SmPCs are warranted in order for these documents to be of reliable use for health care professionals.

Population pharmacokinetic modelling and evaluation of different dosage regimens for darunavir and ritonavir in HIV-infected individuals.

OBJECTIVES: Darunavir is a protease inhibitor that is administered with low-dose ritonavir to enhance its bioavailability. It is prescribed at standard dosage regimens of 600/100 mg twice daily in treatment-experienced patients and 800/100 mg once daily in naive patients. A population pharmacokinetic approach was used to characterize the pharmacokinetics of both drugs and their interaction in a cohort of unselected patients and to compare darunavir exposure expected under alternative dosage regimens. METHODS: The study population included 105 HIV-infected individuals who provided darunavir and ritonavir plasma concentrations. Firstly, a population pharmacokinetic analysis for darunavir and ritonavir was conducted, with inclusion of patients' demographic, clinical and genetic characteristics as potential covariates (NONMEM(®)). Then, the interaction between darunavir and ritonavir was studied while incorporating levels of both drugs into different inhibitory models. Finally, model-based simulations were performed to compare trough concentrations (Cmin) between the recommended dosage regimen and alternative combinations of darunavir and ritonavir. RESULTS: A one-compartment model with first-order absorption adequately characterized darunavir and ritonavir pharmacokinetics. The between-subject variability in both compounds was important [coefficient of variation (CV%) 34% and 47% for darunavir and ritonavir clearance, respectively]. Lopinavir and ritonavir exposure (AUC) affected darunavir clearance, while body weight and darunavir AUC influenced ritonavir elimination. None of the tested genetic variants showed any influence on darunavir or ritonavir pharmacokinetics. The simulations predicted darunavir Cmin much higher than the IC50 thresholds for wild-type and protease inhibitor-resistant HIV-1 strains (55 and 550 ng/mL, respectively) under standard dosing in >98% of experienced and naive patients. Alternative regimens of darunavir/ritonavir 1200/100 or 1200/200 mg once daily also had predicted adequate Cmin (>550 ng/mL) in 84% and 93% of patients, respectively. Reduction of darunavir/ritonavir dosage to 600/50 mg twice daily led to a 23% reduction in average Cmin, still with only 3.8% of patients having concentrations below the IC50 for resistant strains. CONCLUSIONS: The important variability in darunavir and ritonavir pharmacokinetics is poorly explained by clinical covariates and genetic influences. In experienced patients, treatment simplification strategies guided by drug level measurements and adherence monitoring could be proposed.

Medication use in pregnancy: a cross-sectional, multinational web-based study.

OBJECTIVES: Intercountry comparability between studies on medication use in pregnancy is difficult due to dissimilarities in study design and methodology. This study aimed to examine patterns and factors associated with medications use in pregnancy from a multinational perspective, with emphasis on type of medication utilised and indication for use. DESIGN: Cross-sectional, web-based study performed within the period from 1 October 2011 to 29 February 2012. Uniform collection of drug utilisation data was performed via an anonymous online questionnaire. SETTING: Multinational study in Europe (Western, Northern and Eastern), North and South America and Australia. PARTICIPANTS: Pregnant women and new mothers with children less than 1 year of age. PRIMARY AND SECONDARY OUTCOME MEASURES: Prevalence of and factors associated with medication use for acute/short-term illnesses, chronic/long-term disorders and over-the-counter (OTC) medication use. RESULTS: The study population included 9459 women, of which 81.2% reported use of at least one medication (prescribed or OTC) during pregnancy. Overall, OTC medication use occurred in 66.9% of the pregnancies, whereas 68.4% and 17% of women reported use of at least one medication for treatment of acute/short-term illnesses and chronic/long-term disorders, respectively. The extent of self-reported medicated illnesses and types of medication used by indication varied across regions, especially in relation to urinary tract infections, depression or OTC nasal sprays. Women with higher age or lower educational level, housewives or women with an unplanned pregnancy were those most often reporting use of medication for chronic/long-term disorders. Immigrant women in Western (adjusted OR (aOR): 0.55, 95% CI 0.34 to 0.87) and Northern Europe (aOR: 0.50, 95% CI 0.31 to 0.83) were less likely to report use of medication for chronic/long-term disorders during pregnancy than non-immigrants. CONCLUSIONS: In this study, the majority of women in Europe, North America, South America and Australia used at least one medication during pregnancy. There was a substantial inter-region variability in the types of medication used.

Pregnancy outcome following maternal exposure to statins: a multicentre prospective study.

OBJECTIVE: This contribution addresses the risk associated with exposure to statins during pregnancy. DESIGN: Multicentre observational prospective controlled study. SETTING: European Network of Teratology Information Services. POPULATION: Pregnant women who contacted one of 11 participating centres, seeking advice about exposure to statins during pregnancy, or to agents known to be nonteratogenic. METHODS: Pregnancies exposed during first trimester to statins were followed up prospectively, and their outcomes were compared with a matched control group. MAIN OUTCOME MEASURES: Rates of major birth defects, live births, miscarriages, elective terminations, preterm deliveries and gestational age and birthweight at delivery. RESULTS: We collected observations from 249 exposed pregnancies and 249 controls. The difference in the rate of major birth defects between the statin-exposed and the control groups was small and statistically nonsignificant (4.1% versus 2.7% odds ratio [OR] 1.5; 95% confidence interval [95% CI] 0.5-4.5, P = 0.43). In an adjusted Cox model, the difference between miscarriage rates was also small and not significant (hazard ratio 1.36, 95% CI 0.63-2.93, P = 0.43). Premature birth was more frequent in exposed pregnancies (16.1% versus 8.5%; OR 2.1, 95% CI 1.1-3.8, P = 0.019). Nonetheless, median gestational age at birth (39 weeks, interquartile range [IQR] 37-40 versus 39 weeks, IQR 38-40, P = 0.27) and birth weight (3280 g, IQR 2835-3590 versus 3250 g, IQR 2880-3630, P = 0.95) did not differ between exposed and non-exposed pregnancies. CONCLUSIONS: This study did not detect a teratogenic effect of statins. Its statistical power remains insufficient to challenge current recommendations of treatment discontinuation during pregnancy.

Prediction of infant drug exposure through breastfeeding: population PK modeling and simulation of fluoxetine exposure.

The likelihood of significant exposure to drugs in infants through breast milk is poorly defined, given the difficulties of conducting pharmacokinetics (PK) studies. Using fluoxetine (FX) as an example, we conducted a proof-of-principle study applying population PK (popPK) modeling and simulation to estimate drug exposure in infants through breast milk. We simulated data for 1,000 mother-infant pairs, assuming conservatively that the FX clearance in an infant is 20% of the allometrically adjusted value in adults. The model-generated estimate of the milk-to-plasma ratio for FX (mean: 0.59) was consistent with those reported in other studies. The median infant-to-mother ratio of FX steady-state plasma concentrations predicted by the simulation was 8.5%. Although the disposition of the active metabolite, norfluoxetine, could not be modeled, popPK-informed simulation may be valid for other drugs, particularly those without active metabolites, thereby providing a practical alternative to conventional PK studies for exposure risk assessment in this population.

[Drugs and breastfeeding: some facts to consider before deciding they are incompatible]. / Médicaments et allaitement: quelques éléments à considérer avant de les juger incompatibles.

Breastfeeding is considered the ideal way of providing young infants with the required nutrients for healthy growth and development. An increase in the prevalence and duration of breastfeeding has been observed over the last years in response to promotion campaigns. When a medicamentous treatment is started, discontinuation of breastfeeding is often proposed, for fear of harmful consequences for the infant. Nevertheless such a decision is not unimportant, and it appears that many drugs can actually be used during breastfeeding without significant risk. An assessment of the real risk incurred by exposed children makes it possible to avoid unnecessary discontinuations of breastfeeding. This article aims to review the facts needed to assess amount of drug exposure to the child and to list the few drugs associated with significant effects on the nursing infant.

A validated liquid chromatography-mass spectrometry method for the determination of leukotrienes B4 and B5 produced by stimulated human polymorphonuclear leukocytes.

A validated high-performance liquid chromatography (HPLC)-mass spectrometry method has been developed for the simultaneous assay of leukotrienes (LTs) B4 and B5, derived from omega-6 arachidonic acid and omega-3 polyunsaturated fatty acids (PUFA), respectively, produced by human polymorphonuclear leukocytes (PMNLs) stimulated with calcium ionophore A23187. The HPLC separation of PMNL ether extracts was performed on a reversed-phase column using a gradient elution program of 15 mM ammonium acetate and MeOH. Detection was performed by electrospray ionization-single quadripole mass spectrometry using single ion reaction monitoring in the negative mode at m/z 333.3 [M-H](-) and m/z 335.2 for prostaglandin B2/LTB5 and LTB4, respectively. The calibration curves for LTB4 and LTB5 were linear over the ranges 165-990 and 0.825-13.2 ng/ml, respectively. The lower limit of quantification for LTB5 was 0.66 ng/ml. The mean absolute recoveries for LTB4 and LTB5 were 81+/-4.8% and 82+/-5.9%, respectively. The method is precise with mean interday CVs for LTB4 and LTB5 within 7.1-10.7, and 3.8-9.4%, respectively, and accurate (range of interday deviations for LTB4 and LTB5 were -7.8 to 1, and -5 to 9% , respectively). The method has been validated and is being applied to the simultaneous quantification of the leukotrienes B4 and B5 in stimulated PMNLs in a clinical protocol studying the influence of a diet enriched in omega-3 PUFA on various surrogate markers of inflammation in young cystic fibrosis patients.

Tactual extinction without anomia: evidence of attentional factors in a patient with a partial callosal disconnection.

Tactual extinction was examined in a 43-yr-old left-handed male patient (MM) with a hematoma in the trunk of the corpus callosum sparing the genu and the ventral part of the splenium as well as the cerebral hemispheres. Experiments I and II showed no deficit in tactual perception nor in the inter-hemispheric transfer of tactual information. In Experiment III, MM palpated stimuli differing in their association value, and responded vocally or manually. There was no difference in performance between the hands in unimanual control conditions, but in a dichhaptic condition an overall right-hand advantage was observed, depending on the kind of stimulus and on the mode of response: such results were not observed in control subjects. Results showed that MM's left-hand performance reached right-hand levels after specific modifications in the allocation of attention between the hands or the load of information in haptic memory (Experiment IV). Experiment V revealed a major deficit in the matching of left- and right-hand information only for the dichhaptic procedure. The results are discussed with a view of cerebral mechanisms as dynamic rather than structurally determined: it is suggested that extinction phenomena are sensitive to cognitive strategies and attentional factors and that the corpus callosum plays a critical role in the lateral control of attention to tactual as well as to auditory and visual information.