The current study was conducted to compare the efficacy of prophylactic intravenous versus oral (Cephradin) for the prevention of surgical site infections (SSI) in Obstetric and Gynecological interventions.

A randomized clinical trial was carried out on 230 patients fulfilling the eligibility criteria between 1st October 2023 and 31st July 2024, including pregnant women who were approached prior to their delivery and non-pregnant women who were approached prior to their intended interventions. (group A) 116 patients received oral antimicrobial prophylaxis, while (group B) 114 patients received intravenous antimicrobial prophylaxis. Furthermore, all included patients received oral antibiotics postoperatively (oral cephradine 500 mg/ 12 h for 7 days). Patients were evaluated twice; the 1st assessment was done 1 week, while the 2nd assessment was done a month after the intervention.

SSI rate was 14 % CI (0.07-0.20) in the oral group compared to 13 % CI (0.07-0.20) in the intravenous group after one week with no significant difference in between (p = 0.84). However, the SSI rate was 5.5 % CI (0.02-0.11) in the oral group compared to 6.3 % CI (0.02-0.12) in the intravenous group after one month of the intervention, with no significant difference in between (p = 0.78).

The current study showed that oral antibiotic prophylaxis before obstetric and gynecological interventions seems to be safe, easy, practical, cheap, and as effective as parenteral antibiotic prophylaxis in the prevention of SSI. However, more randomized trials with larger sample sizes are needed to pave the way for replacing parenteral with oral antibiotic chemoprophylaxis.

The study was approved by the Sohag Ethical Committee, Faculty of Medicine, with IRB number (Soh-Med-23-09-05MS) and was registered on clinical trial.gov with T.R.N (NCT06255652).

Sustained fetal tachycardia requires transplacental anti-arrhythmic therapy. Little is known about the dose-concentration-effect correlation and safety in the mother, fetus, and newborn.

This study evaluates the relationship between maternal dose of digoxin and flecainide therapy for fetal tachycardia, maternal and umbilical cord concentrations, and side effects.

This was a retrospective case series. We included 28 pregnant women initially treated with digoxin monotherapy for fetal tachycardia between June 2007 and January 2023. The main end point was the correlation between maternal drug exposure, effect, and side effects.

Oral digoxin monotherapy converted 9 fetuses (32%) to sinus rhythm after a median of 4.5 days (interquartile range [IQR] 3-6.5). Overall, 18 fetuses required additional oral flecainide (300 mg daily), resulting in a total conversion rate of 93% (26/28). Equal starting doses of digoxin caused similar maternal digoxin concentrations regardless of gestational age, with no significant difference between responders and non-responders (P = .504). Side effects, primarily nausea, led to dose reductions, but treatment remained effective. Maternal digoxin concentrations remained stable throughout pregnancy and little inter-patient variability was observed. Flecainide exposure varied both within and between patients. The median fetus/mother digoxin ratio was similar in both monotherapy (n = 3) and combination (n = 9) therapy groups (0.51 (IQR 0.28-0.76) vs 0.45 (IQR 0.39-0.64), P = .864). The median fetus/mother flecainide ratio was 0.82 (IQR 0.69-1.29).

Digoxin monotherapy successfully treated fetal tachycardia in only 32% of cases. Adding flecainide improved response to 93%, although it increased side effects, which could be managed with dose reductions. Maternal digoxin levels were stable throughout pregnancy.

Background: Cancer-related pain management in pregnant patients is a complex clinical challenge requiring a careful balance between effective maternal analgesia and fetal safety. The pathophysiology of cancer-related pain varies, necessitating a nuanced, individualized approach to treatment with careful consideration of maternal-fetal safety, and pharmacokinetics. Objectives: This review aims to explore safe and effective pharmacological and interventional strategies for managing cancer-related pain in pregnant patients while highlighting disparities in access to care. Design: A comprehensive literature review was conducted. A total of 4766 articles were identified, with 98 studies included for final analysis after exclusion. Setting/Subjects: Studies included pregnant individuals with various hematological and solid tumor malignancies across various community and academic settings. Measurements: Pain typology was categorized (nociceptive or neuropathic), with treatment options including commonly available over-the-counter medications, opioids, various neuropathic medications, and interventional pain management options. In addition to pharmacological efficacy and maternofetal safety profiles, interventional efficacy, and socio-cultural influences on care were also measured. Disparities in access to care were also analyzed. Results: Analgesic options in pregnancy include acetaminophen, opioids, certain neuropathic medications, with very cautious use of NSAIDs. Interventional methods-neuraxial anesthesia, nerve blocks, spinal cord stimulation-offer adjunctive benefit if done under ultrasound guidance, but fluoroscopy and radiation guided modalities are best avoided in pregnancy. Diverse populations often encountered significant barriers to adequate pain control. Conclusions: Optimal cancer pain management in pregnancy necessitates a multidisciplinary, and individually tailored approach. Enhancing clinical evidence, and ensuring culturally competent care are critical to improving outcomes in this patient population.

Levofloxacin is a key drug in the prevention and treatment of rifampicin-resistant tuberculosis (RR-TB). There are limited data describing the effect of pregnancy on the pharmacokinetics of levofloxacin. We aimed to characterize the pharmacokinetics of levofloxacin in adults with RR-TB, including the effect of pregnancy. We pooled data from two studies conducted in adult participants treated for RR-TB in South Africa. Treatment regimens in both studies included levofloxacin dosed at 750/1000 mg daily, depending on body weight. We analyzed data from 47 participants, 31 (66%) living with HIV, using nonlinear mixed-effects modeling in NONMEM v7.5.1. Out of 33 female participants, 21 were pregnant, of whom 12 contributed matched antepartum and postpartum pharmacokinetic profiles. Levofloxacin followed one-compartment pharmacokinetics with first-order elimination and absorption with transit absorption compartments. The clearance and volume of distribution for a typical non-pregnant participant (weight: 58 kg; age: 32 years; serum creatinine: 56.2 µmol/L) were 6.06 (95% confidence interval [CI], 5.47 to 6.53) L/h and 85.9 (95% CI, 80.6 to 91.7) L, respectively. Higher serum creatinine levels were associated with lower levofloxacin clearance using a power function with an exponent of -0.367 (95% CI, -0.493 to -0.104). Pregnancy increased levofloxacin clearance by 38.1% (95% CI, 23.4% to 57.1%), with substantially lower exposures in pregnant compared with non-pregnant participants receiving equivalent weight-based doses. To achieve non-pregnant equivalent exposures of levofloxacin, an additional 250 mg tablet may be required, although further study is needed to assess the safety implications of a higher recommended dose in pregnant women.

Pharmacotherapy of maternal peripartum depression is an increasing challenge. Amitriptyline (AMI) is the most often used tricyclic antidepressant during pregnancy, but knowledge on pharmacokinetics in this special phase is lacking. Physiologically based pharmacokinetic (PBPK) modelling is a powerful tool to better understand pregnancy-induced pharmacokinetic changes of medication. We aimed to improve the knowledge about AMI pharmacokinetics during pregnancy using PBPK modelling. Consequently, we aimed to add new information for an effective and safe pharmacotherapy in pregnant women.

A PBPK model, including AMI, but also its active metabolite nortriptyline (NOR), was developed to investigate pregnancy-induced pharmacokinetic changes after AMI administration. The predicted drug exposure was compared to observed concentrations in pregnant patients in clinical routine. The PBPK model was set up using PK-Sim Version 11.

Serum concentration profiles were described successfully. During pregnancy, active moiety serum concentration of AMI (AMI + NOR) did not change; however, AMI concentration increased, whereas NOR concentration decreased.

With this model, we added valuable information on AMI pharmacokinetics during pregnancy (increased AMI concentration, decreased NOR concentration). For clinical practice the treating physician should be aware that despite active moiety serum concentration comparable to before pregnancy, tolerability may be affected due to increased AMI serum concentrations and as consequence increased anticholinergic effects. To keep the risk of therapy discontinuation during pregnancy low, we suggest performing therapeutic drug monitoring, especially to check the AMI serum concentration.

Pregnancy alters the systemic exposure and clearance of many hepatically cleared drugs that are commonly used by obstetric patients. Understanding the molecular mechanisms underlying the changes in factors that affect hepatic drug clearance (blood flow, protein binding, and intrinsic clearance) is essential to more precisely predict systemic drug exposure and dose requirements in obstetric patients.

This review (1) summarizes the anatomic, physiologic, and biochemical changes in maternal hepatic, cardiovascular, endocrine, and renal systems relevant to hepatic drug clearance and (2) reviews the molecular mechanisms underlying the altered hepatic metabolism and intrinsic clearance of drugs during pregnancy via a comprehensive PubMed search. It also identifies knowledge gaps in the molecular mechanisms and factors that modulate hepatic drug clearance during pregnancy.

Pharmacokinetic studies have shown that pregnancy alters systemic exposure, protein binding, and clearance of many drugs during gestation in part due to pregnancy-associated decreases in plasma albumin, increases in organ blood flow, and changes in the activity of drug-metabolizing enzymes (DMEs) and transporters. The changes in the activity of certain DMEs and transporters during pregnancy are likely driven by hormonal-changes that inhibit their activity or alter the expression of these proteins through activation of transcription factors.

Pregnant women have historically been excluded from participation in medication trials, in part due to the perceived risks of drug exposure to mothers and fetuses. However, little is known about pregnant women's attitudes toward risk and participation in such trials.

To address this knowledge gap and to identify factors that influence trial participation.

Australian women over the age of 18, currently pregnant or within six months of delivery, were recruited to participate in an online survey (n = 623) and follow-up interviews (n = 11). The survey investigated willingness to participate in five hypothetical drug trial scenarios of varying risk. Demographic and obstetric information, including COVID-19 vaccination status, was also collected. The impact of these factors on trial participation was analysed using ordinal regression. Interviews were subjected to thematic framework analysis using a priori and emergent themes.

Nearly half of the respondents (48%) indicated a willingness to participate in at least one of the hypothetical trials. As trial risk increased participation likelihood decreased, especially if the risk was to the fetus, regardless of benefits to the mother. COVID-19 vaccination status and medication hesitancy were predictors of an unwillingness to participate. Three broad themes emerged from the qualitative data: risk-benefit analysis, quality of evidence, and trust.

Overall, participants expressed a positive attitude toward research and medication trials during pregnancy, but were concerned about fetal risk. The findings of this study may help enhance trial design and the participation of pregnant women in medication trials.

In recent years, medication use during pregnancy has increased, yet its association with maternal characteristics remains unclear. To address this gap, we aimed to investigate how maternal age, pre-gestational body mass index (BMI), smoking, parity, ethnic origin and employment status relate to medication use during pregnancy. We conducted a nationwide Danish registry study, including 698 447 clinically recognised pregnancies with a gestational age of at least 10 weeks, spanning from 2008 to 2018. Medication use was estimated based on prescription redemptions during pregnancy and stratified by the demographic factors of interest. Overall, 60.3% of pregnant women redeemed at least one prescription, while 28.9% redeemed multiple medications. Notably, higher usage was observed among women aged 35 or older, those with a BMI of 30 kg/m2 or more, smokers, multipara, Black women, and early retirees. Medication combination patterns differed with the demographic subgroups. These findings highlight notable differences in medication use among demographic groups during pregnancy, underscoring the need for tailored healthcare strategies during pregnancy.

The management of haematological malignancies in pregnancy represents a complex medical challenge. These rare conditions require multidisciplinary collaboration to address both the maternal risks associated with physiological changes and the foetal risks, such as malformations or prematurity associated with treatment. However, data to guide the care of these patients are still limited. Comprehensive research is needed to better understand these diseases, assess the impact of treatments and optimise care, including the involvement of pregnant patients in clinical trials to improve their access to innovative therapies. This article provides an overview of the issues involved in the management of haematological malignancies during pregnancy, highlighting the diagnostic, therapeutic and prognostic challenges.

Model-informed precision dosing (MIPD) utilizes mathematical models to predict optimal medication doses for a specific patient or patient population. However, the factors influencing the implementation of MIPD have not been fully elucidated, hindering its widespread use in clinical practice. A systematic review was conducted in PubMed from inception to December 2022, aiming to identify barriers and facilitators for the implementation of MIPD into patient care. Articles with a focus on implementation of MIPD were eligible for this review. After screening titles and abstracts, full articles investigating the clinical implementation of MIPD were included for data extraction. Of 790 records identified, 15 publications were included. A total of 72 barriers and facilitators across seven categories were extracted through a hybrid thematic analysis. Barriers comprised limited data for model validation, unclear regulatory pathways for model endorsement and additional drug level measurements required for certain types of MIPD. Facilitators encompassed the development of user-friendly MIPD tools continuously updated based on user feedback and data. Collaborative efforts among diverse stakeholders for model validation and implementation, along with education of end-users, may promote the utilization of MIPD in patient care. Despite ongoing challenges, this systematic review revealed various strategies to facilitate the clinical implementation of MIPD.

Although exposure to metals remains a public health concern, few studies have examined exposure to combinations of metals. This study characterized prevalent combinations of cadmium (Cd), mercury (Hg), and lead (Pb) in women (n = 10,152; aged 20-44 years) who participated in the U.S. National Health and Nutrition Examination Survey (NHANES) 1999-2018. To explore relative metal exposures within this population, Cd, Hg, and Pb blood levels were dichotomized as "high" and "low" categories using median values to represent the center of the metal concentrations in the study population, not thresholds for adverse health effects. The prevalence of the three metal combinations at "high" levels (singular, binary, tertiary combinations) was calculated. Multinomial logistic regression was used to calculate odds ratios for each combination relative to none of these combinations after adjusting for potential confounders. Among the pregnant women (n = 1297), singular Hg was most prevalent (19.2% [95% CI 15.0-23.3]), followed by singular Cd (14.7% [95% CI 11.2-18.2]), tertiary combination Cd/Hg/Pb (11.0% [95% CI 8.7-13.2]), binary combinations Cd/Pb (9.8% [95% CI 7.4-12.2]), Hg/Pb (9.2% [95% CI 6.5-11.8]), Cd/Hg (7.8% [95% CI 6.0-9.6]), and singular Pb (5.5% [95% CI 4.1-6.9]). We found significantly lower odds of having Cd/Hg/Pb (adjusted odds ratio (adjOR) = 0.49: p < 0.001) and Cd/Pb (adjOR = 0.68: p < 0.0364) combinations among pregnant women compared to non-pregnant women. The odds of having higher levels of singular Pb were significantly lower (adjOR = 0.31: p < 0.0001) in women pregnant in their first and second trimesters (n = 563) than in non-pregnant women (n = 6412), whereas, though nonsignificant, the odds were higher for women pregnant in their third trimester (n = 366) (adjOR = 1.25: p = 0.4715). These results indicate the possibility that the fetus might be exposed to higher levels of the metal mixtures due to placental transfer, particularly to Pb, during the early stages of pregnancy. Further research is warranted to understand the relationship between metal combination exposures during pregnancy and maternal and infant health.

Cytochrome P450 (CYP) 3A4 is an essential drug-metabolizing enzyme in humans, which shows substantial interindividual variation in response to various intrinsic and extrinsic factors such as sex and pregnancy. In humans, higher CYP3A4 metabolism has been observed in females compared with that in males and in pregnant compared with that in nonpregnant individuals, which has been linked to increased CYP3A4 expression in liver. However, sex differences and pregnancy-mediated changes in hepatic CYP3A4 expression and activity in vivo are not fully understood. In this study, we investigated the utility of a genetically engineered humanized mouse model that carries human CYP3A4/7, pregnane X receptor (PXR) and constitutive androstane receptor (CAR) (huPXR/CAR/CYP3A4/7) to recapitulate sex-associated and pregnancy-associated differences in the hepatic CYP3A4 expression and metabolism observed in humans. We found that female huPXR/CAR/CYP3A4/7 mice exhibited higher basal CYP3A4 mRNA levels and CYP3A4 absolute protein concentrations in liver, and higher 1-hydroxymidazolam formation in liver microsomes, compared with male humanized mice. In contrast, pregnant huPXR/CAR/CYP3A4/7 mice exhibited lower CYP3A4 mRNA levels, CYP3A4 absolute protein concentrations, and 1-hydroxymidazolam formation compared with nonpregnant and postpartum humanized mice. Expression of CAR and Cyp2b10 (a CAR responsive gene) were also higher in females and decreased during pregnancy and were positively correlated with hepatic CYP3A4 mRNA levels. Overall, the huPXR/CAR/CYP3A4/7 mouse model demonstrated utility to study higher basal hepatic CYP3A4 metabolism in females compared with that in males in vivo; however, this humanized mouse model did not demonstrate utility to study pregnancy-mediated increases in CYP3A4 drug substrate metabolism and clearance observed in humans. SIGNIFICANCE STATEMENT: This study assessed the impact of sex and pregnancy on hepatic CYP3A4 protein concentrations and metabolism in humanized PXR/CAR/CYP3A4 mice. Consistent with humans, female mice demonstrated higher hepatic CYP3A4 expression and activity than male mice. In contrast, pregnant mice showed decreased CYP3A4 expression and metabolism compared with nonpregnant mice. The humanized mouse model appeared useful to evaluate sex differences in basal hepatic CYP3A4 metabolism in vivo, but not to study the pregnancy-mediated increase in CYP3A4 metabolism observed during human pregnancy.

Limited data are available on VWF activity (VWF:Act) and factor VIII (FVIII:C) levels during delivery after VWF/FVIII concentrate administration in women with von Willebrand disease (VWD). We aimed to evaluate treatment with a specific VWF/FVIII concentrate on factor levels in women with VWD during delivery and the postpartum period. A retrospective single-center study was conducted between January 1, 2008, and August 1, 2022. Pregnant women treated with Haemate®P during delivery were included if they had ≥2 consecutive VWF:Act and FVIII:C measurements post-infusion. VWF:Act/FVIII:C levels were compared to predefined target levels. A population pharmacokinetic (PopPK) model was developed, estimating VWF and FVIII pharmacokinetics after Haemate®P administration. Nineteen women were included. Targeted VWF:Act/FVIII:C peak levels were achieved after the first infusion (≥1.00 IU/mL, n = 12; ≥1.50 IU/mL, n = 5), and all VWF:Act/FVIII:C trough levels remained ≥0.50 IU/mL during first 72 h of treatment. All women had pretreatment FVIII:C levels ≥1.00 IU/mL, except one woman with type 2N, which was significantly higher than FVIII:C levels during the third trimester (median increase: 0.42 IU/mL, interquartile range: [0.12-0.92]). FVIII:C trough levels increased during treatment, median 2.05 IU/mL [1.65-2.71]. Nine women (47%) experienced postpartum hemorrhage and no thrombosis occurred. A one-compartment PopPK model adequately described VWF:Act/FVIII:C levels. Targeted VWF:Act/FVIII:C peak levels were achieved with the prescribed dosing regimens. VWF clearance was similar to that in nonpregnant individuals. Both pretreatment and FVIIIC trough levels during treatment were high with reduced FVIII clearance. Monitoring VWF:Act/FVIII:C levels is recommended for optimizing target levels and enriching the current PopPK model, improving VWF:Act/FVIII:C level predictions, and achieving more effective dosing.

Small interfering RNA (siRNA) therapeutics represent an emerging class of pharmacotherapy with the potential to address previously hard-to-treat diseases. Currently approved siRNA therapeutics include lipid nanoparticle-encapsulated siRNA and tri-N-acetylated galactosamine-conjugated siRNA. These siRNA therapeutics exhibit distinct pharmacokinetic characteristics and unique absorption, distribution, metabolism, and elimination (ADME) properties. As a new drug modality, limited clinical data are available for siRNA therapeutics in specific populations, including pediatrics, geriatrics, individuals with renal or hepatic impairment, and pregnant women, making dosing challenging. In this Minireview, a mechanistic overview of the ADME properties of the 5 currently approved siRNA therapeutics is presented. A concise overview of the clinical data available for therapeutic siRNAs in special populations, focusing on the potential impact of physiologic changes during pregnancy on siRNA disposition, is provided. The utility of physiologically based pharmacokinetic (PBPK) modeling as a tool to elucidate the characteristics and disposition of siRNA therapeutics in pregnant women is explored. Additionally, opportunities to integrate known physiologic alterations induced by pregnancy into PBPK models that incorporate siRNA ADME mechanisms to predict the effects of pregnancy on siRNA disposition are discussed. Clinical data regarding the use of therapeutic siRNA in special populations remain limited. Data for precise parameterization of maternal-fetal siRNA PBPK models are lacking presently and underscore the need for further research in this area. Addressing this gap in knowledge will not only enhance our understanding of siRNA pharmacokinetics during pregnancy but also advance the possible development of siRNA therapeutics to treat pregnancy-related conditions. SIGNIFICANCE STATEMENT: This Minireview proposes a framework on how small interfering RNA (siRNA) disposition can be predicted in pregnancy based on mechanistic absorption, distribution, metabolism, and elimination (ADME) information using physiologically-based pharmacokinetic (PBPK) modeling. The mechanistic ADME information and available clinical data in special populations of currently Food and Drug Administration-approved siRNA therapeutics are summarized. Additionally, how physiological changes during pregnancy may affect siRNA disposition is reviewed, and the opportunities to use PBPK modeling to predict siRNA disposition in pregnant women is explored.

Despite growing knowledge of pregnancy-induced changes in physiology that may alter maternal and fetal pharmacokinetics, evidence-based antenatal doses are lacking for most drugs. Pharmacokinetic modeling and expanding clinical data in pregnancy may support antenatal doses. We aimed to develop and pilot a comprehensive and user-driven Framework for Dose Selection in Pregnancy to support the clinical implementation of a best-evidence antenatal dose for sertraline. After initial development and evaluation by experts, the framework prototype was piloted to formulate an antenatal dosing strategy for sertraline in depression and anxiety disorders. Next, the framework was reviewed and assessed for usability by a multidisciplinary working committee of end-users comprising healthcare practitioners, experts from other disciplines including pharmacometrics, reproductive toxicology and medical ethics, alongside pregnant women and a partner. The resulting framework encompasses the following: rationale for drug selection, a comprehensive analysis of pharmacokinetic and dose-related efficacy and safety data, and implementation aspects including feasibility and desirability of the recommended antenatal dose based on a structured maternal and fetal benefit-risk assessment. An antenatal dose recommendation for sertraline, as a case study, was formulated using this approach and endorsed for clinical use by the working committee. Future applications of the framework for other drugs can further demonstrate its suitability for developing best evidence, acceptable and clinically feasible antenatal doses.

Dolutegravir (DTG) is an antiviral agent used for the treatment of HIV, however, there is uncertainty over the influence of genetic variation on DTG exposure, and whether it has clinical implications for the efficacy or toxicity in different populations. This systematic review aims to create an overview of the impact of pharmacogenomics (PGx) on DTG exposure, efficacy, and toxicity.

Publications up to 14 November 2023 were searched and articles were selected on the following criteria: original research articles providing data on people with HIV, data on PGx and either PK or PD or both PD and PGx.

711 records were identified, and after screening 10 articles were included. Commonly analyzed genes across the articles were UGT1A1, ABCB1, ABCG2, and NR1I2. The most reported variant associated with PD variability was in SLC22A2, with carriers at higher risk of neuropsychiatric adverse events.

This review concludes that while PGx testing may help explain some variability in DTG pharmacokinetics when combined with therapeutic drug monitoring (TDM), current evidence is insufficient to support its routine clinical use. The role of PGx research for DTG remains relevant, especially in specific patient populations where interindividual PK variations are still unexplained.

Introduction: Despite advances in obstetric care, postpartum hemorrhage (PPH) is a leading cause of maternal mortality worldwide. Prior reviews of studies published through 2016 suggest an association of antidepressant use during late pregnancy and increased risk of PPH. However, a causal link between prenatal antidepressants and PPH remains controversial. Objectives: This systematic literature review aimed to synthesize the empirical evidence on the association of antidepressant exposure in late pregnancy with the risk of PPH, including studies published before and after 2016. Methods: A systematic literature search was conducted using PubMed, OVID Medline, EMBASE, SCOPUS, PsycINFO, and CINAHL from inception to September 9, 2023. Original, peer-reviewed studies (published in English) that reported on the frequency or risk of PPH in women with evidence of antidepressant use during pregnancy and included at least one control group were included. Results: Twenty studies (eight published after 2016) met inclusion criteria, most of which focused on the risks of PPH associated with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). The main findings from the individual studies were mixed, but the majority documented statistically significant associations of PPH with late prenatal exposure, especially for exposures occurring within 30 days of delivery, compared with unexposed deliveries. Fourteen studies addressed underlying antidepressant indications or their correlates. Few studies focused on prenatal antidepressants and the risk of well-defined severe PPH or on antidepressant dose changes and general PPH risk. None examined competing risks of antidepressant discontinuation on mental health outcomes. Conclusions: Late pregnancy exposure to antidepressants may be a minor risk factor for PPH, but it is unclear to what extent reported associations are causal in nature, as opposed to correlational (effects related to nonpharmacological factors including maternal indication). For patients needing antidepressants during pregnancy, current evidence does not favor routinely discontinuing antidepressants specifically to reduce the risk of PPH.

Most individuals use medication during pregnancy. However, decision making on antenatal pharmacotherapy presents considerable ethical and scientific challenges. Amid a sociocultural paradigm prioritising the elimination of fetal risks, available evidence and guidance are limited, and current decision making on antenatal drugs mostly proceeds in an ad-hoc and, often, biased manner. This approach might undermine the health of both mother and child. The need for a systematic approach towards antenatal drug decisions is becoming even more pressing with the growing knowledge of pregnancy-induced changes in drug disposition and effects. With this new complexity, pregnancy-specific doses might be necessary, potentially altering the balance between maternal and fetal benefits and risks. In this Viewpoint, we argue that ethical principles and a pregnant individual's values must be integrated alongside existing evidence when making decisions on antenatal drug use and dosing. We use the example of sertraline to outline practical strategies for achieving this goal. This approach is urgently needed to foster better-informed and balanced decisions on antenatal pharmacotherapy.

The ex vivo human placenta perfusion model has proven to be clinically relevant to study transfer- and fetal exposure of various drugs. Although the method has existed for a long period, the setup of the perfusion model has not been generalized yet. This review aims to summarize the setups of ex vivo placental perfusion models used to examine drug transfer across the placenta to identify generalized properties and differences across setups. A literature search was carried out in PubMed September 26, 2022. Studies were labeled as relevant when information was reported, between 2000 and 2022, on the setups of ex vivo placental perfusion models used to study drug transfer across the placenta. The placenta perfusion process, and the data extraction, was divided into phases of preparation, control, drug, and experimental reflecting the chronological timeline of the different phases during the entire placental perfusion process. 135 studies describing an ex vivo human placental perfusion experiment were included. Among included studies, the majority (78.5%) analyzed drug perfusion in maternal to fetal direction, 18% evaluated bi-directional drug perfusion, 3% under equilibrium conditions, and one study investigated drug perfusion in fetal to maternal direction. This literature review facilitates the comparison of studies that employ similar placenta perfusion protocols for drug transfer studies and reveals significant disparities in the setup of these ex vivo placental perfusion models. Due to interlaboratory variability, perfusion studies are not readily comparable or interchangeable. Therefore, a stepwise protocol with multiple checkpoints for validating placental perfusion is needed.

Prenatal drug use may cause toxicity to bone health in newborns. We aimed to examine whether birth outcomes mediate the association between medication use and neonatal metabolic bone disease (MBD).

A prospective cohort of 10,801 pregnant women (17-49 years) and their infants followed at a single center from 1 January 2012 to 31 December 2021 were included. Based on four single drugs, comprehensive medication use was determined and categorized into three groups using latent-class analysis: group 1 included antibiotics and furosemide or less than two drugs except for MgSO4; group 2 included MgSO4 without antibiotics or furosemide; and group 3 encompassed dexamethasone and antibiotics. Mediation analysis was conducted to assess the mediating effects of prematurity, low birth weight (LBW), and small for gestational age (SGA).

There were 138 (1.3%) infants with MBD; 2,701 (25%) were born preterm, 1717 (15.9%) had LBW, and 303 (2.8%) were SGA. Pregnant women in groups 2 and 3 were 2.52 to 14.66 times more likely to deliver an infant with MBD than those in group 1. Only LBW showed a significant mediating effect on the association between comprehensive medication use and MBD, with a mediation proportion of 51.8% (45.0-64.1%, p < 0.001).

Comprehensive medication use during pregnancy was associated with an increased risk of neonatal MBD, largely mediated by LBW. Early antepartum monitoring and prevention targeting adverse birth outcomes are necessary to mitigate the risk of MBD.

This study aimed to model the pharmacokinetics of lamotrigine (LTG) and efavirenz (EFV) in pregnant women using physiologically based pharmacokinetic (PBPK) and pregnancy-specific PBPK (p-PBPK) models. For lamotrigine, the adult PBPK model demonstrated accurate predictions for pharmacokinetic parameters. Predictions for the area under the curve (AUC) and peak plasma concentration (Cmax) generally agreed well with observed values. During pregnancy, the PBPK model accurately predicted AUC and Cmax with a prediction error (%PE) of less than 25%. The evaluation of the EFV PBPK model revealed mixed results. While the model accurately predicted certain parameters for non-pregnant adults, significant discrepancies were observed in predictions for higher doses (600 vs. 400 mg) and pregnant individuals. The model's performance during pregnancy was poor, indicating the need for further refinement to account for genetic polymorphism. Gender differences also influenced EFV pharmacokinetics, with lower exposure levels in females compared to males. These findings highlight the complexity of modeling EFV, in general, but specifically in pregnant populations, and the importance of validating such models for accurate clinical application. The study highlights the importance of tailoring dosing regimens for pregnant individuals to ensure both safety and efficacy, particularly when using combination therapies with UGT substrate drugs. Although drug-drug interactions between LTG and EFV appear minimal, further research is needed to improve predictive models and enhance their accuracy.

Background: Physiological changes in pregnancy may affect drug safety and efficacy, sometimes requiring dose adjustments. Pregnancy-adjusted doses, however, are missing for most medications. Increasingly, pharmacokinetic models can be used for antenatal dose finding. Given the novelty of this technique and questions regarding dose credibility, the acceptability of model-informed antenatal doses should be explored. Objective: We aimed to assess the willingness-to-use and preferred features for model-informed antenatal doses among healthcare practitioners (HCPs) and pregnant women in European countries. Methods: A cross-sectional, web-based study drawing on two open surveys was performed between 8 September and 30 November 2022. Each survey comprised statements drawn from prior focus groups, associated with Likert-scales. Themes included respondents' information needs, search behaviours along with their willingness-to-use and preferred features for model-informed antenatal doses. The surveys were disseminated through professional societies, pregnancy websites and social media. A descriptive analysis was performed. Results: In total, 608 HCPs from different specialties and 794 pregnant women across 15 countries participated, with 81% of respondents across both groups in the Netherlands or Belgium. Among pregnant women, 31% were medical professionals and 85% used medication during pregnancy. Eighty-three percent of HCPs found current antenatal pharmacotherapy suboptimal and 97% believed that model-informed antenatal doses would enhance the quality of antenatal care. Most HCPs (93%) and pregnant women (75%) would be willing to follow model-informed antenatal doses. Most HCPs desired access to the evidence (88%), including from pharmacokinetic modelling (62%). Most pregnant women (96%) wanted to understand antenatal dosing rationales and to be involved in dosing decisions (97%). Conclusion: The willingness-to-use model-informed antenatal doses is high among HCPs and pregnant women provided that certain information needs are met.

Limited information exists regarding the impact of pharmacotherapy in pregnancy due to ethical concerns of unintended fetal harm. Yet, maternal prescriptive drug use for chronic conditions such as hypertension is common.

To investigate potential causal relationships between perturbing maternal genetic variants influencing antihypertensive drug targets and perinatal outcomes among offspring using mendelian randomization (MR).

This 2-sample MR study used individual-level single-nucleotide variation (SNV) outcome data from mother-father-offspring trios with complete genetic and phenotypic information from the Norwegian Mother, Father and Child Cohort Study (MoBa) and summary-level SNV exposure data from UK Biobank participants sourced from the Integrative Epidemiology Unit OpenGWAS project. Pregnant individuals were recruited across Norway during their routine ultrasonography examination at 18 weeks' gestation between June 1999 and December 2008, and mothers, fathers, and offspring were followed up after birth. Novel genetic instruments for maternal antihypertensive drug targets that act via systolic blood pressure (SBP) were derived from individual-level data analyzed in January 2018. Two-sample multivariable MR analysis of these maternal drug targets and offspring outcomes were performed between January 2023 and April 2024.

Maternal genetic variants associated with drug targets for treatments of hypertension, as specified in the National Health Service dictionary of medicines and devices.

Offspring outcomes were Apgar score at 1 minute and 5 minutes, offspring developmental score at 6 months, birth length, birth weight z score, gestational age, head circumference, and congenital malformation. Maternal hypertensive disorders of pregnancy were a positive control.

The MoBa sample contained 29 849 family trios, with a mean (SD) maternal age of 30.2 (18.6) years and a mean (SD) paternal age of 32.8 (13.1) years; 51.1% of offspring were male. Seven independent SNVs were identified as influencing maternal SBP via the antihypertensive drug target instruments. For higher levels of maternal SBP acting through the CACNB2 calcium channel blocker target, the estimated change in gestational age was 3.99 days (95% CI, 0.02-7.96 days) per 10-mm Hg decrease in SBP. There was no evidence of differential risk for measured perinatal outcomes from maternal SBP acting through drug targets for multiple hypertensive subclasses, such as between the ADRB1 β-adrenoceptor-blocking target and risk of congenital malformation (estimated odds ratio, 0.28 [95% CI, 0.02-4.71] per 10-mm Hg decrease in SBP). Maternal and paternal SBP acting through the EDNRA vasodilator antihypertensive target did not have a potential causal effect on birth weight z score, with respective β estimates of 0.71 (95% CI, -0.09 to 1.51) and 0.72 (95% CI, -0.08 to 1.53) per 10-mm Hg decrease in SBP.

The findings provided little evidence to indicate that perturbation of maternal genetic variants for SBP that influence antihypertensive drug targets had potential causal relationships with measures of perinatal development and health within this study. These findings may be triangulated with existing literature to guide physicians and mothers in decisions about antihypertensive use during pregnancy.

Epilepsy is a disorder of recurrent, unprovoked seizures affecting approximately 15 million individuals of childbearing potential worldwide. Patients with epilepsy rely on regular daily therapy with antiseizure medications (ASMs). Furthermore, ASMs are also prescribed for other neuropsychiatric indications (e.g. bipolar disorder, pain, migraines) with over 2% of the pregnancies in the United States involving prenatal exposure to ASMs.

ASM concentrations are affected by hormonal and physiological changes in pregnancy, including increases in renal and hepatic blood flow, decreased protein binding, and changes in enzyme activity. Clearance changes typically reverse within a few weeks after delivery. During pregnancy, many ASMs, such as lamotrigine, levetiracetam, and oxcarbazepine, should have serum concentrations monitored and doses increased to maintain the individualized target range for seizure control. ASMs metabolized via glucuronidation, primarily lamotrigine, undergo marked increases in clearance throughout pregnancy, requiring about 3-fold the pre-pregnancy daily dose by delivery. Postpartum, ASM doses are usually decreased over several weeks to prevent drug toxicity.

In the future, the development of a physiologically-based pharmacokinetic model for various ASMs may enable empiric dose adjustments in pregnancy without the difficulties of frequent therapeutic drug monitoring.

The relationship between multifetal cesarean delivery and surgical-site infection (SSI) is unclear. If SSI is more common in multifetal cesareans, adjustment of practices such as antibiotic dosing could be warranted. The purpose of this study was to determine whether patients undergoing multifetal cesarean delivery are more likely to experience SSI than those undergoing singleton cesarean delivery.

This was a retrospective cohort study including all cesarean deliveries at a tertiary hospital from 10/1/2009 to 12/28/2018. The primary outcome was rate of SSI in women after multifetal cesarean delivery as compared to those who underwent singleton cesarean delivery. Univariable analysis and multivariable logistic regression were used to assess independent clinical factors associated with SSI in multifetal cesarean deliveries.

34,340 women underwent cesarean delivery during this period. 33,211 were singletons (96.7%), and 1,129 were multifetal (3.3%). There was no difference in the rate of SSI in multifetal gestations (15/1,129, 1.3%) as compared to singletons (493/33,211, 1.5%) (p = 0.670, OR 0.89 [95% CI 0.53, 1.50], aOR 1.06 [95% CI 0.61, 1.84]). Limiting analysis to multifetal deliveries, prolonged rupture of membranes (p < 0.004, OR 5.43 [95% CI 1.49, 19.88]), labor augmentation (p < 0.001, OR 15.84 [1.74, 144.53]), and chorioamnionitis (p < 0.001, OR 15.43 [95% CI 3.11, 76.62]) were more common in women with SSI.

SSI is not increased in multifetal cesarean delivery as compared to singleton cesarean delivery. In multifetal cesareans, chorioamnionitis, prolonged rupture of membranes, and labor augmentation were associated with increased odds of SSI.

The challenges of drug development in pediatric, pregnant and geriatric populations are a worldwide concern shared by regulatory authorities, pharmaceutical companies, and healthcare professionals. Model-informed drug development (MIDD) can integrate and quantify real-world data of physiology, pharmacology, and disease processes by using modeling and simulation techniques to facilitate decision-making in drug development. In this article, we reviewed current MIDD policy updates, reflected on the integrity of physiological data used for MIDD and the effects of physiological changes on the drug PK, as well as summarized current MIDD strategies and applications, so as to present the state of the art of MIDD in pediatric, pregnant and geriatric populations. Some considerations are put forth for the future improvements of MIDD including refining regulatory considerations, improving the integrity of physiological data, applying the emerging technologies, and exploring the application of MIDD in new therapies like gene therapies for special populations.

Advancements in psychotropic therapy for pregnant women are pivotal for addressing maternal mental health during the perinatal period. Screening for mood and anxiety symptoms during pregnancy is recommended to enable early intervention. Psychotropic medications, including antidepressants, benzodiazepines, antipsychotics, and mood stabilizers, are commonly used, but challenges remain regarding their safety and efficacy during pregnancy. Pregnancy induces significant changes in pharmacokinetics, necessitating personalized dosing strategies and careful monitoring. Real-time monitoring technologies, such as smartphone-integrated platforms and home-based monitoring, enhance accessibility and accuracy. Prospective studies and collaboration among healthcare providers are essential for evidence-based guidelines and optimal treatment strategies. Reducing stigma around mental health during pregnancy is crucial to ensure women seek help and discuss treatment options, promoting understanding and acceptance within the community.

Addressing the complexities of managing viral infections during pregnancy is essential for informed medical decision-making. This comprehensive review delves into the management of key viral infections impacting pregnant women, namely Human Immunodeficiency Virus (HIV), Hepatitis B Virus/Hepatitis C Virus (HBV/HCV), Influenza, Cytomegalovirus (CMV), and SARS-CoV-2 (COVID-19). We evaluate the safety and efficacy profiles of antiviral treatments for each infection, while also exploring innovative avenues such as gene vaccines and their potential in mitigating viral threats during pregnancy. Additionally, the review examines strategies to overcome challenges, encompassing prophylactic and therapeutic vaccine research, regulatory considerations, and safety protocols. Utilizing advanced methodologies, including PBPK modeling, machine learning, artificial intelligence, and causal inference, we can amplify our comprehension and decision-making capabilities in this intricate domain. This narrative review aims to shed light on diverse approaches and ongoing advancements, this review aims to foster progress in antiviral therapy for pregnant women, improving maternal and fetal health outcomes.

Increasing evidence suggests that the physiological changes of pregnancy may impact pharmacokinetics of antiseizure medications (ASM), and this may affect treatment outcomes. The aim of this study was to quantify the pregnancy impact on the ASM pharmacokinetics.

A systematic literature search was conducted in PubMed/EMBASE in November 2022 and updated in August 2023 for studies comparing levels of ASM in the same individuals during pregnancy and in the preconception/postpartum period. Alteration ratios between the 3rd trimester and baseline were estimated. We also performed a random-effects meta-analysis calculating between-timepoint differences in mean differences (MDs) and 95% confidence intervals (95%CIs) for dose-adjusted plasma concentrations (C/D ratios). Study quality was assessed using the ClinPK guidelines.

A total of 65 studies investigating 15 ASMs in 674 pregnancies were included. The largest differences were reported for lamotrigine, oxcarbazepine and levetiracetam (alteration ratio 0.42, range 0.07-2.45, 0.42, range 0.08-0.82 and 0.52, range 0.04-2.77 respectively): accordingly, C/D levels were lower in the 3rd trimester for lamotrigine, levetiracetam and the main oxcarbazepine metabolite monohydroxycarbazepine (MD = -12.33 × 10-3, 95%CI = -16.08 to -8.58 × 10-3 (μg/mL)/(mg/day), p < 0.001, MD = -7.16 (μg/mL)/(mg/day), 95%CI = -9.96 to -4.36, p < 0.001, and MD = -4.87 (μg/mL)/(mg/day), 95%CI = -9.39 to -0.35, p = 0.035, respectively), but not for oxcarbazepine (MD = 1.16 × 10-3 (μg/mL)/(mg/day), 95%CI = -2.55 to 0.24 × 10-3, p = 0.10). The quality of studies was acceptable with an average rating score of 11.5.

Data for lamotrigine, oxcarbazepine (and monohydroxycarbazepine) and levetiracetam demonstrate major changes in pharmacokinetics during pregnancy, suggesting the importance of therapeutic drug monitoring to assist clinicians in optimizing treatment outcomes.

Maternal mortality rates are at an all-time high across the world and are set to increase in subsequent years. Cardiovascular disease is the leading cause of death during pregnancy and postpartum, especially in the United States. Therefore, understanding the physiological changes in the cardiovascular system during normal pregnancy is necessary to understand disease-related pathology. Significant systemic and cardiovascular physiological changes occur during pregnancy that are essential for supporting the maternal-fetal dyad. The physiological impact of pregnancy on the cardiovascular system has been examined in both experimental animal models and in humans. However, there is a continued need in this field of study to provide increased rigor and reproducibility. Therefore, these guidelines aim to provide information regarding best practices and recommendations to accurately and rigorously measure cardiovascular physiology during normal and cardiovascular disease-complicated pregnancies in human and animal models.

Familial chylomicronemia syndrome (FCS) is a rare inherited disorder characterized by severe hypertriglyceridemia, posing a heightened risk of acute pancreatitis. Recently, Volanesorsen, an APOC3 antisense oligonucleotide, gained approval for FCS treatment in the UK. Caution is advised during pregnancy due to limited safety data, although animal studies show no toxicity/teratogenicity. Two case scenarios are presented: In the first case, a patient with FCS continued Volanesorsen injections without having thrombocytopenia during an unplanned pregnancy until third trimester, maintaining triglyceride control. Upon discovering the pregnancy at 38 weeks, Volanesorsen was ceased, and a low-fat diet reinstated. Despite a heightened risk of pancreatitis, no episodes of pancreatitis occurred during the pregnancy. In the second case, stopping Volanesorsen before conception led to elevated triglycerides, and an episode of acute pancreatitis at 22 weeks, despite strict very low-fat diet and fibrate therapy from 14 weeks. At 23 weeks, Volanesorsen was reintroduced concurrently with regular therapeutic plasma exchange. No further episodes of pancreatitis occurred. In both case, fetal health was maintained throughout pregnancy, fetal scans revealed no anomalies, and planned C-sections delivered healthy babies without congenital issues. Both babies are well and developing normally at 24 and 19 months.

Expression of the breast cancer resistance protein (BCRP/ABCG2) transporter is downregulated in placentas from women with preeclampsia (PE) and in an immunological rat model of PE. While many drugs are substrates of this important efflux transporter, the impact of PE associated BCRP downregulation on maternal and fetal drug exposure has not been investigated. Using the PE rat model, we performed a pharmacokinetic study with rosuvastatin (RSV), a BCRP substrate, to investigate this impact. PE was induced in rats during gestational days (GD) 13 to 16 with daily low-dose endotoxin. On GD18, RSV (3 mg/kg) was administrated intravenously, and rats were sacrificed at time intervals between 0.5 and 6 h. As compared to controls, placental expression of Bcrp and Oatp2b1 significantly decreased in PE rats. A corresponding increase in RSV levels was seen in fetal tissues and amniotic fluid of the PE group (p < 0.05), while maternal plasma concentrations remained unchanged from the controls. An increase in Bcrp expression and decreased RSV concentration were seen in the livers of PE dams. This suggests that PE-mediated transporter dysregulation leads to significant changes in the maternal and fetal RSV disposition. Overall, our findings demonstrate that altered placental expression of transporters in PE can increase fetal accumulation of their substrates.

Most women use medication during pregnancy. Pregnancy-induced changes in physiology may require antenatal dose alterations. Yet, evidence-based doses in pregnancy are missing. Given historically limited data, pharmacokinetic models may inform pregnancy-adjusted doses. However, implementing model-informed doses in clinical practice requires support from relevant stakeholders.

To explore the perceived barriers and facilitators for model-informed antenatal doses among healthcare practitioners (HCPs) and pregnant women.

Online focus groups and interviews were held among healthcare practitioners (HCPs) and pregnant women from eight countries across Europe, Africa and Asia. Purposive sampling was used to identify pregnant women plus HCPs across various specialties prescribing or providing advice on medication to pregnant women. Perceived barriers and facilitators for implementing model-informed doses in pregnancy were identified and categorised using a hybrid thematic analysis.

Fifty HCPs and 11 pregnant women participated in 12 focus groups and 16 interviews between January 2022 and March 2023. HCPs worked in the Netherlands (n = 32), the UK (n = 7), South Africa (n = 5), Uganda (n = 4), Kenya, Cameroon, India and Vietnam (n = 1 each). All pregnant women resided in the Netherlands. Barriers and facilitators identified by HCPs spanned 14 categories across four domains whereas pregnant women described barriers and facilitators spanning nine categories within the same domains. Most participants found current antenatal dosing information inadequate and regarded model-informed doses in pregnancy as a valuable and for some, much-needed addition to antenatal care. Although willingness-to-follow model-informed antenatal doses was high across both groups, several barriers for implementation were identified. HCPs underlined the need for transparent model validation and endorsement of the methodology by recognised institutions. Foetal safety was deemed a critical knowledge gap by both groups. HCPs' information needs and preferred features for model-informed doses in pregnancy varied. Several pregnant women expressed a desire to access information and partake in decisions on antenatal dosing.

Given the perceived limitations of current pharmacotherapy for pregnant women and foetuses, model-informed dosing in pregnancy was seen as a promising means to enhance antenatal care by pregnant women and healthcare practitioners.

The placenta exerts a crucial role in fetus growth and development during gestation, protecting the fetus from maternal drugs and chemical exposure. However, diverse drugs and chemicals (xenobiotics) can penetrate the maternal placental barrier, leading to deleterious, adverse effects concerning fetus health. Moreover, placental enzymes can metabolize drugs and chemicals into more toxic compounds for the fetus. Thus, evaluating the molecular mechanisms through which drugs and chemicals transfer and undergo metabolism across the placental barrier is of vital importance. In this aspect, this comprehensive literature review aims to provide a holistic approach by critically summarizing and scrutinizing the potential molecular processes and mechanisms governing drugs and chemical transfer and metabolism across the placental barrier, which may lead to fetotoxicity effects, as well as analyzing the currently available experimental methodologies used to assess xenobiotics placental transfer and metabolism.

A comprehensive and in-depth literature review was conducted in the most accurate scientific databases such as PubMed, Scopus, and Web of Science by using relevant and effective keywords related to xenobiotic placental transfer and metabolism, retrieving 8830 published articles until 5 February 2024. After applying several strict exclusion and inclusion criteria, a final number of 148 relevant published articles were included.

During pregnancy, several drugs and chemicals can be transferred from the mother to the fetus across the placental barrier by either passive diffusion or through placental transporters, resulting in fetus exposure and potential fetotoxicity effects. Some drugs and chemicals also appear to be metabolized across the placental barrier, leading to more toxic products for both the mother and the fetus. At present, there is increasing research development of diverse experimental methodologies to determine the potential molecular processes and mechanisms of drug and chemical placental transfer and metabolism. All the currently available methodologies have specific strengths and limitations, highlighting the strong demand to utilize an efficient combination of them to obtain reliable evidence concerning drug and chemical transfer and metabolism across the placental barrier. To derive the most consistent and safe evidence, in vitro studies, ex vivo perfusion methods, and in vivo animal and human studies can be applied together with the final aim to minimize potential fetotoxicity effects.

Research is being increasingly carried out to obtain an accurate and safe evaluation of drug and chemical transport and metabolism across the placental barrier, applying a combination of advanced techniques to avoid potential fetotoxic effects. The improvement of the currently available techniques and the development of novel experimental protocols and methodologies are of major importance to protect both the mother and the fetus from xenobiotic exposure, as well as to minimize potential fetotoxicity effects.

Physiologically based pharmacokinetic (PBPK) modelling in pregnancy is a relatively new approach that is increasingly being used to assess drug systemic exposure in pregnant women to potentially inform dosing adjustments. Physiological changes throughout pregnancy are incorporated into mathematical models to simulate drug disposition in the maternal and fetal compartments as well as the transfer of drugs across the placenta. This mini-review gathers currently available pregnancy PBPK models for drugs commonly used during pregnancy. In addition, information about the main PBPK modelling platforms used, metabolism pathways, drug transporters, data availability and drug labels were collected. The aim of this mini-review is to provide a concise overview, demonstrate trends in the field, highlight understudied areas and identify current gaps of PBPK modelling in pregnancy. Possible future applications of this PBPK approach are discussed from a clinical, regulatory and industry perspective.

Unfractionated heparin is a widely used anticoagulant in critically ill patients. It has a well-established safety profile and remains an attractive option for clinicians due to its short half-life and reversibility. Heparin has a unique pharmacokinetic profile, which contributes to significant inter-patient and intra-patient variability in effect. The variability in anticoagulant effect combined with heparin's short half-life mean close monitoring is required for clinical efficacy and preventing adverse effects. To optimize heparin use in critically ill patients, effective monitoring assays and dose adjustment strategies are needed.

This paper explores the use of heparin as an anticoagulant and optimal approaches to monitoring in critically ill patients.

Conventional monitoring assays for heparin dosing have significant limitations. Emerging data appear to favor using anti-Xa assay monitoring for heparin anticoagulation, which many centers have successfully adopted as the standard. The anti-Xa assay appears have important benefits relative to the aPTT for heparin monitoring in critically ill patients, and should be considered for broader use.

Arrhythmic mitral valve prolapse (AMVP) is linked to life-threatening ventricular arrhythmias (VAs), and young women are considered at high risk. Cases of AMVP in women with malignant VA during pregnancy have emerged, but the arrhythmic risk during pregnancy is unknown. The authors aimed to describe features of women with high-risk AMVP who developed malignant VA during the perinatal period and to assess if pregnancy and the postpartum period were associated with a higher risk of malignant VA.

This retrospective international multi-centre case series included high-risk women with AMVP who experienced malignant VA and at least one pregnancy. Malignant VA included ventricular fibrillation, sustained ventricular tachycardia, or appropriate shock from an implantable cardioverter defibrillator. The authors compared the incidence of malignant VA in non-pregnant periods and perinatal period; the latter defined as occurring during pregnancy and within 6 months after delivery.

The authors included 18 women with AMVP from 11 centres. During 7.5 (interquartile range 5.8-16.6) years of follow-up, 37 malignant VAs occurred, of which 18 were pregnancy related occurring in 13 (72%) unique patients. Pregnancy and 6 months after delivery showed increased incidence rate of malignant VA compared to the non-pregnancy period (univariate incidence rate ratio 2.66, 95% confidence interval 1.23-5.76).

The perinatal period could impose increased risk of malignant VA in women with high-risk AMVP. The data may provide general guidance for pre-conception counselling and for nuanced shared decision-making between patients and clinicians.

Selective Serotonin Reuptake Inhibitors (SSRIs) are widely used medications for the treatment of major depressive disorder. However, long-term SSRI use has been associated with weight gain and altered lipid profiles. These findings suggest that SSRIs may have negative effects on metabolism. Exposure to certain chemicals called 'obesogens' is known to promote lipid accumulation and obesity by modulating adipogenesis. Here, we investigated whether citalopram (CIT) and sertraline (SER) interfere with the process of adipogenesis, using human mesenchymal stem cells (MSCs) in a 2D and a 3D model. Assessment of intracellular lipid accumulation by fluorescence staining was used as a measure for enhanced adipogenesis. To explore possible mechanisms behind SSRIs' effects, receptor mediated activity was studied using responsive cell lines for various nuclear receptors. Furthermore, RNA sequencing was performed in the 3D model, followed by differential gene expression and pathway analysis. A dose dependent increase in lipid accumulation was observed in both models with CIT and SER. For the 3D model, the effect was seen in a range close to reported steady-state plasma concentrations (0.065-0.65 μM for SER and 0.12-0.92 μM for CIT). Pathway analysis revealed unexpected results of downregulation in adipogenesis-related pathways and upregulation in phospholipids and lysosomal pathways. This was confirmed by an observed increase in lysosomes in the 2D model. Our findings suggest lysosomal dysfunction and disrupted lipid metabolism in mature adipocytes, leading to excessive phospholipid synthesis. Moreover, important adipogenic processes are inhibited, potentially leading to dysfunctional adipocytes, which might have implications in the maintenance of a healthy metabolic balance.