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Per- and polyfluoroalkyl substances (PFAS) can pass through the placenta and adversely affect fetal development. However, there is a lack of comparison of legacy and emerging PFAS levels among different biosamples in pregnant women and their offspring. This study, based on the Shanghai Maternal–Child Pairs Cohort, analyzed the concentrations of 16 PFAS in the maternal serum, cord serum, and breast milk samples from 1,076 mother-child pairs. The placental and breastfeeding transfer efficiencies of PFAS were determined in maternal-cord and maternal-milk pairs, respectively. The binding affinities of PFAS to five transporters were simulated using molecular docking. The results suggested that PFAS were frequently detected in different biosamples. The median concentration of perfluorooctane sulfonate (PFOS) was the highest at 8.85 ng/mL, followed by perfluorooctanoic acid (PFOA) at 7.13 ng/mL and 6:2 chlorinated polyfluorinated ether sulfonate at 5.59 ng/mL in maternal serum. The median concentrations of PFOA were highest in cord serum (4.23 ng/mL) and breast milk (1.08 ng/mL). PFAS demonstrated higher placental than breastfeeding transfer efficiencies. The transfer efficiencies and the binding affinities of most PFAS to proteins exhibited alkyl chain length-dependent patterns. Furthermore, we comprehensively assessed the estimated daily intakes (EDIs) of PFAS in breastfeeding infants of different age groups and used the hazard quotient (HQ) to characterize the potential health risk. EDIs decreased with infant age, and PFOS had higher HQs than PFOA. These findings highlight the significance of considering PFAS exposure, transfer mechanism, and health risks resulting from breast milk intake in early life.

In the present study, we evaluated the influence of maternal and neonatal factors on the efficiency of the placental transfer of neutralizing antibodies against SARS-CoV-2. Vaccination during pregnancy provides fetal and neonatal protection through the passive transplacental transfer of maternal neutralizing antibodies. To date, little information is available regarding the factors that affect the transfer of antibodies against SARS-CoV-2. A retrospective, cross-sectional, observational, and analytical study was carried out. It was found that several biological factors could be altering transplacental passive immunity after vaccination against COVID-19. In our study population, type 2 diabetes mellitus and chronic hypertension tended to decrease efficiency, while data from women with pre-eclampsia showed better indices compared to those from women with healthy pregnancies. Neonates born prematurely showed lower transfer rates when compared to healthy neonates. The premature rupture of membranes significantly decreased antibody transfer. Taken together, the data suggest that vaccination against COVID-19 during pregnancy is effective even under certain unfavorable clinical conditions for the mother, fetus, and neonate. It is important to create and disseminate immunization strategies in vulnerable populations to reduce maternal and perinatal morbidity and mortality associated with infections preventable by vaccination. [ABSTRACT FROM AUTHOR]

Abstract Purpose Pregnant women are at risk of severe SARS-CoV-2 infection, potentially leading to obstetric and neonatal complications. Placental transfer of antibodies directed to SARS-CoV-2 may be protective against neonatal COVID-19, but this remains to be studied. We aimed to determine the seroprevalence of SARS-CoV-2 antibodies in a population of unvaccinated pregnant women and to determine the placental transfer of these antibodies. Methodology A total of 1197 unvaccinated women with mostly unknown pre-study SARS-CoV-2 infection status, were tested at delivery for SARS-CoV-2 spike protein IgG antibodies during the first year of the pandemic. Umbilical cord samples were collected and assessed for seropositivity if the mother was seropositive. Maternal characteristics, pregnancy and neonatal outcomes and data on SARS-CoV-2 infection were extracted from medical records. Results Specific IgG were detected in 258 women (21.6%). A significant placental transfer to the newborn was observed in 81.3% of cases. The earlier in the 2nd and 3rd trimesters that the mother had contracted the disease and the more symptomatic she was, the greater the likelihood of transplacental transfer of IgG to her newborn. Conclusion Approximately one in five women had detectable anti-SARS-CoV-2 spike protein IgG antibodies at delivery during the first year of the pandemic, and these antibodies were significantly transferred to their fetuses. This research provides further evidence to better understand the dynamics of the placental transfer of SARS-CoV-2 IgG antibodies from mothers to their newborns, which is necessary to improve vaccination strategies.

Purpose: Pregnant women are at risk of severe SARS-CoV-2 infection, potentially leading to obstetric and neonatal complications. Placental transfer of antibodies directed to SARS-CoV-2 may be protective against neonatal COVID-19, but this remains to be studied. We aimed to determine the seroprevalence of SARS-CoV-2 antibodies in a population of unvaccinated pregnant women and to determine the placental transfer of these antibodies. Methodology: A total of 1197 unvaccinated women with mostly unknown pre-study SARS-CoV-2 infection status, were tested at delivery for SARS-CoV-2 spike protein IgG antibodies during the first year of the pandemic. Umbilical cord samples were collected and assessed for seropositivity if the mother was seropositive. Maternal characteristics, pregnancy and neonatal outcomes and data on SARS-CoV-2 infection were extracted from medical records. Results: Specific IgG were detected in 258 women (21.6%). A significant placental transfer to the newborn was observed in 81.3% of cases. The earlier in the 2nd and 3rd trimesters that the mother had contracted the disease and the more symptomatic she was, the greater the likelihood of transplacental transfer of IgG to her newborn. Conclusion: Approximately one in five women had detectable anti-SARS-CoV-2 spike protein IgG antibodies at delivery during the first year of the pandemic, and these antibodies were significantly transferred to their fetuses. This research provides further evidence to better understand the dynamics of the placental transfer of SARS-CoV-2 IgG antibodies from mothers to their newborns, which is necessary to improve vaccination strategies. Highlights: - In our large cohort of unvaccinated women, almost ten times the size of the largest previously published study, one in five women had detectable anti-SARS-CoV-2 spike protein IgG antibodies at delivery during the first year of the pandemic. - Four out of five women transferred these anti-SARS-CoV-2 spike protein IgG antibodies towards their fetuses. - The earlier the mother was infected—in the 2nd and 3rd trimester—the higher her antibody level, and the more symptomatic she was, the greater the likelihood of transplacental transfer of IgG to her newborn. - As placental transfer is variable and depends on several factors, understanding the dynamics of antibody transfer and its impact on fetal health following a natural SARS-CoV-2 infection, can improve vaccination strategies to optimize neonatal protection. [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR) may affect placental transfer of key nutrients to the fetus, such as the fatty acid docosahexaenoic acid (DHA). Major facilitator superfamily domain containing 2A (MFSD2A) has been described as a specific DHA carrier in placenta, but its expression has not been studied in FGR. The aim of this study was to evaluate for the first time the placental MFSD2A levels in late-FGR pregnancies and the maternal and cord plasma DHA. 87 pregnant women from a tertial reference center were classified into late-FGR (N = 18) or control (N = 69). Fatty acid profile was determined in maternal and cord venous plasma, as well as placental levels of MFSD2A and of insulin mediators like phospho-protein kinase B (phospho-AKT) and phospho-extracellular regulated kinase (phospho-ERK). Maternal fatty acid profile did not differ between groups. Nevertheless, late-FGR cord vein presented higher content of saturated fatty acids than control, producing a concomitant decrease in the percentage of some unsaturated fatty acids. In the late-FGR group, a lower DHA fetal/maternal ratio was observed when using percentages, but not with concentrations. No alterations were found in the expression of MFSD2A in late-FGR placentas, nor in phospho-AKT or phospho-ERK. MFSD2A protein expression was not altered in late-FGR placentas, in line with no differences in cord DHA concentration between groups. The increase in the saturated fatty acid content of late-FGR cord might be a compensatory mechanism to ensure fetal energy supply, decreasing other fatty acids percentage. Future studies are warranted to elucidate if altered saturated fatty acid profile in late-FGR fetuses might predispose them to postnatal catch-up and to long-term health consequences. • First study about placental MFSD2A levels in fetal growth restriction. • Fetuses with late-FGR presented higher content of saturated fatty acids. • No alterations in placental MFSD2A or fetal DHA concentration in late-FGR. [ABSTRACT FROM AUTHOR]

The placenta is a membrane that separates the fetus from the maternal circulation, and in addition to protecting the fetus, plays a key role in fetal growth and development. With increasing drug use in pregnancy, it is imperative that reliable models of estimating placental permeability and safety be established. In vitro methods and animal models such as rodent placenta are limited in application since the species-specific nature of the placenta prevents meaningful extrapolations to humans. In this regard, in silico approaches such as quantitative structure-property relationships (QSPRs) are useful alternatives. However, despite evidence that drug transport across the placenta is stereoselective (i.e., governed by the spatial arrangement of the atoms in a molecule), many QSPR models for placental transfer have been built using 2D descriptors that do not account for chirality and stereochemistry. In this study, we apply a chirality-sensitive and proven QSPR methodology titled "EigenValue ANalySis" (EVANS) to build QSPR models for placental transfer. We deploy EVANS along with robust machine learning algorithms to build (i) regression models on a dataset of environmental chemicals (dataset PD I) followed by (ii) classification models on a set of drug-like compounds (dataset PD II). The best models were found to achieve state-of-the-art performance, with the support vector machine algorithm returning r train 2 = 0.85 , r test 2 = 0.75 for PD I, and the logistic regression algorithm giving accuracy 0.88 and F1 score 0.93 for PD II. The best models were interpreted with the Shapley Additive Explanations paradigm, and it was found that autocorrelation descriptors are crucial for modelling placental permeability. In conclusion, we demonstrate the need of a chirality-sensitive approach for modelling placental transfer of chemicals, and present two predictive QSPR models that may reliably be used for prediction of placental transfer. • A chirality-sensitive methodology titled "EigenValue ANalySis" (EVANS) is applied to build QSPR models for placental transfer • SVM regression models on a dataset of environmental chemicals returned r train 2 = 0.85 , r test 2 = 0.75 • Logistic regression models on a set of drug-like compounds had accuracy 0.88 and F1 score 0.93 • We demonstrate the need of a chirality-sensitive approach for modelling placental transfer of chemicals [ABSTRACT FROM AUTHOR]

Aim/objective: This study investigates placental antibody transfer following recombinant pertussis vaccination in pregnancy in a real-world setting. Methods: This postmarketing observational study recruited pregnant women vaccinated with monovalent recombinant acellular pertussis (aP) vaccine (aPgen; n = 199) or combined to tetanus-diphtheria (TdaPgen; n = 200), or Td-vaccine only (n = 54). Pregnancy, delivery, and neonatal outcomes were assessed. Cord blood was collected postdelivery and pertussis toxin (PT)-IgG, filamentous hemagglutinin (FHA)-IgG, and PT-neutralizing antibodies (PT-Nab) were assessed. Results: No adverse pregnancy, delivery, or neonatal outcomes attributed to aPgen, TdaPgen, or Td vaccination were reported. High anti-PT antibody levels were detected in cord samples from women vaccinated with aPgen (geometric mean concentration [GMC] PT-IgG 206.1 IU/ml, 95% confidence intervals [CI]: 164.3-258.6; geometric mean titer [GMT] PT-Nab 105.3 IU/ml, 95% CI: 81.7-135.8) or TdaPgen (GMC PT-IgG 153.1 IU/ml, 95% CI: 129.1-181.5; GMT PT-Nab 81.5 IU/ml, 95% CI: 66.4-100.0). In the Td-only group, anti-PT antibodies were low (GMC PT-IgG 6.5 IU/ml, 95% CI: 4.9-8.8; GMT PT-Nab 3.8 IU/ml, 95% CI: 2.8-5.1). The same was found for FHA-IgG. Recombinant pertussis vaccination at

The protection of the neonate against pathogens depends largely on the antibodies transferred placentally from the mother; for this reason, maternal vaccination against emerging viruses, such as SARS-CoV-2, is of vital importance. Knowing some of the immunogenic factors that could alter the placental transfer of antibodies could aid in understanding the immune response and neonatal protection after maternal vaccination. In this study, we analyzed the efficiency of the placental transfer of binding and neutralizing antibodies, as well as some factors that could alter the passive immune response, such as the trimester of gestation at the time of immunization, the number of doses received by the mother and the type of vaccine. Binding IgG antibodies were detected by ELISA, and the detection of neutralizing antibodies was carried out using flow cytometry. Our results show efficient transfer rates (>1), which are higher when maternal vaccination occurs during the third trimester of gestation. Antibodies are detectable in mothers and their neonates after 12 months of maternal immunization, suggesting than the vaccination against COVID-19 before and during pregnancy in the Mexican population induces a lasting neutralizing response in mothers and their newborns. [ABSTRACT FROM AUTHOR]

The transplacental passage of cells between a mother and her fetus, known as microchimerism, is a less studied process during pregnancy. The frequency of maternal microchimeric cells in fetal tissues in physiological pregnancies and mechanisms responsible for transplacental cell trafficking are poorly understood. This study aimed to evaluate the placental trafficking of maternal peripheral blood mononuclear cells (PBMC) using human ex vivo placenta perfusion. Ten placentas and maternal PBMC were obtained after healthy pregnancies. Flow cytometry was used to characterize PBMC subtypes. They showed a higher percentage of CD3+ T cells compared to CD56+ NK cells. The isolated PBMC were stained with a fluorescent dye and perfused through the maternal circuit of the placenta in an ex vivo perfusion system. Subsequent immunofluorescence staining for CD3+ T cells and CD56+ NK cells was performed on placental tissue sections, and the number of detectable PBMC in different tissue areas was counted using fluorescence microscopy. The applied method allowed discrimination of perfused autologous maternal cells from cells resident in the placenta before perfusion. Further, it allows additional immunohistochemical labelling and distinction of immune cell subsets. Perfused PBMC were detected in all analyzed placentas, mostly in contact to the syncytiotrophoblast. CD3+ T cells were identified more frequently than CD56+ NK cells and some CD3+ T cells were found inside fetoplacental tissues and vasculature. The results indicate that also other PBMCs than T or NK cells adhere to or enter villous tissue, but they have not been specified in this analysis. Previous studies have detected maternal cells in the fetal circulation which we could mimick in our ex vivo placenta perfusion experiments with fluorescence labelled autologous maternal PBMC. The applied experimental settings did not allow comparison of transmigration abilities of PBMC subsets, but slight modifications of the model will permit further studies of cell transfer processes and microchimerism in pregnancy. • Ex vivo placenta perfusion is useful for testing materno-fetal cell transfer. • Maternal immune cells cross the placental barrier. • Maternal NK cells migrate into placental villi. • Maternal T cells migrate through placental villi and enter fetal vessels. • Placental cell transfer leads to microchimerism. [ABSTRACT FROM AUTHOR]

Context Vitamin D inadequacy is globally prevalent among pregnant women; however, its impact on pregnancy remains inconclusive. Objective This study aims to explore the associations of maternal and umbilical cord serum 25-hydroxyvitamin D (25(OH)D) levels with pregnancy and neonatal outcomes. Method We used archived serum samples from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study participants in the Hong Kong center and assayed maternal 25(OH)D levels at midgestation and umbilical cord 25(OH)D at birth using liquid chromatography–tandem mass spectroscopy. Data regarding pregnancy and perinatal outcomes were extracted from the HAPO study dataset and the hospital computerized medical system. Results Only 247 (16.4%) mothers and 66 (5.0%) neonates met the criteria for vitamin D sufficiency (ie, 25(OH)D ≥ 75 nmol/L). The ratio of umbilical cord to maternal vitamin D levels was positively associated with maternal age and ambient solar radiation at the month of delivery, while negatively associated with maternal serum total 25(OH)D at midgestation (all P <.001). Umbilical cord serum 25(OH)D was independently associated with a lower primary cesarean section rate (OR 0.990, 95% CI 0.982-0.999; P =.032). There were no associations of maternal and umbilical cord 25(OH)D levels with other adverse pregnancy and neonatal outcomes. Conclusion Placental vitamin D transfer was found to be higher with a lower maternal vitamin D level, older maternal age, and higher ambient solar radiation at the time of the delivery. The protective effect of sufficient vitamin D in a cesarean section will require further studies. [ABSTRACT FROM AUTHOR]

Establishing an immune balance between the mother and fetus during gestation is crucial, with the placenta acting as the epicenter of immune tolerance. The placental transfer of antibodies, mainly immunoglobulin G (IgG), is critical in protecting the developing fetus from infections. This review looks at how immunomodulation of antibody glycosylation occurs during placental transfer and how it affects fetal health. The passage of maternal IgG antibodies through the placental layers, including the syncytiotrophoblast, stroma, and fetal endothelium, is discussed. The effect of IgG subclass, glycosylation, concentration, maternal infections, and antigen specificity on antibody transfer efficiency is investigated. FcRn-mediated IgG transport, influenced by pH-dependent binding, is essential for placental transfer. Additionally, this review delves into the impact of glycosylation patterns on antibody functionality, considering both protective and pathological effects. Factors affecting the transfer of protective antibodies, such as maternal vaccination, are discussed along with reducing harmful antibodies. This in-depth examination of placental antibody transfer and glycosylation provides insights into improving neonatal immunity and mitigating the effects of maternal autoimmune and alloimmune conditions. [ABSTRACT FROM AUTHOR]

In the present study, we evaluated the influence of maternal and neonatal factors on the efficiency of the placental transfer of neutralizing antibodies against SARS-CoV-2. Vaccination during pregnancy provides fetal and neonatal protection through the passive transplacental transfer of maternal neutralizing antibodies. To date, little information is available regarding the factors that affect the transfer of antibodies against SARS-CoV-2. A retrospective, cross-sectional, observational, and analytical study was carried out. It was found that several biological factors could be altering transplacental passive immunity after vaccination against COVID-19. In our study population, type 2 diabetes mellitus and chronic hypertension tended to decrease efficiency, while data from women with pre-eclampsia showed better indices compared to those from women with healthy pregnancies. Neonates born prematurely showed lower transfer rates when compared to healthy neonates. The premature rupture of membranes significantly decreased antibody transfer. Taken together, the data suggest that vaccination against COVID-19 during pregnancy is effective even under certain unfavorable clinical conditions for the mother, fetus, and neonate. It is important to create and disseminate immunization strategies in vulnerable populations to reduce maternal and perinatal morbidity and mortality associated with infections preventable by vaccination.

Background: Pregnancy is associated with a higher risk of adverse symptoms and outcomes for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection for both mother and neonate. Antibodies can provide protection against SARS-CoV-2 infection and are induced in pregnant women after vaccination or infection. Passive transfer of these antibodies from mother to fetus in utero may provide protection to the neonate against infection. However, it is unclear whether the magnitude or quality and kinetics of maternally derived fetal antibodies differs in the context of maternal infection or vaccination. Objective: We aimed to determine whether antibodies transferred from maternal to fetus differed in quality or quantity between infection- or vaccination-induced humoral immune responses. Methods: We evaluated 93 paired maternal and neonatal umbilical cord blood plasma samples collected between October 2020 and February 2022 from a birth cohort of pregnant women from New Orleans, Louisiana, with histories of SARS-CoV-2 infection and/or vaccination. Plasma was profiled for the levels of spike-specific antibodies and induction of antiviral humoral immune functions, including neutralization and Fc-mediated innate immune effector functions. Responses were compared between 4 groups according to maternal infection and vaccination. Results: We found that SARS-CoV-2 vaccination or infection during pregnancy increased the levels of antiviral antibodies compared to naive subjects. Vaccinated mothers and cord samples had the highest anti-spike antibody levels and antiviral function independent of the time of vaccination during pregnancy. Conclusions: These results show that the most effective passive transfer of functional antibodies against SARS-CoV-2 in utero is achieved through vaccination, highlighting the importance of vaccination in pregnant women.

ABSTRACTNerve growth factor (NGF) has emerged as a key driver of pain perception in several chronic pain conditions, including osteoarthritis (OA), and plays an important role in the generation and survival of neurons. Although anti-NGF antibodies improve pain control and physical function in patients with clinical chronic pain conditions, anti-NGF IgGs are associated with safety concerns such as effects on fetal and postnatal development and the risk of rapidly progressive osteoarthritis. To overcome these drawbacks, we generated a novel anti-NGF PEGylated Fab’ antibody. The anti-NGF PEGylated Fab’ showed specific binding to and biological inhibitory activity against NGF, and analgesic effects in adjuvant-induced arthritis model mice in a similar manner to an anti-NGF IgG. In collagen-induced arthritis model mice, the anti-NGF PEGylated Fab’ showed higher accumulation in inflamed foot pads than the anti-NGF IgG. In pregnant rats and non-human primates, the anti-NGF PEGylated Fab’ was undetectable in fetuses, while the anti-NGF IgG was detected and caused abnormal postnatal development. The PEGylated Fab’ and IgG also differed in their ability to form immune complexes in vitro. Additionally, while both PEGylated Fab’ and IgG showed analgesic effects in sodium monoiodoacetate-induced arthritic model rats, their effects on edema were surprisingly quite different. While the anti-NGF IgG promoted edema over time, the anti-NGF PEGylated Fab’ did not. The anti-NGF PEGylated Fab’ (ASP6294) may thus be a potential therapeutic candidate with lower risk of adverse effects for various diseases in which NGF is involved such as OA and chronic back pain.

Background In a phase 1/2 study, a maternal respiratory syncytial virus vaccine candidate (RSVPreF3) demonstrated an acceptable safety profile and efficiently increased RSV-specific humoral immune responses in non-pregnant women. Methods In this phase 2 observer-blind, placebo-controlled, randomized clinical trial (NCT04126213), the safety of RSVPreF3 (60 or 120 µg), administered during late second or third trimester, was evaluated in 213 18- to 40-year-old healthy pregnant women through 6 months postdelivery and their offspring through infancy; immunogenicity was evaluated through day 43 postdelivery and day 181 postbirth, respectively. Results RSVPreF3 was well tolerated. No pregnancy-related or neonatal adverse events of special interest were considered vaccine/placebo related. In the 60 and 120 µg RSVPreF3 groups: (1) neutralizing antibody (nAb) titers in mothers increased 12.7- and 14.9-fold against RSV-A and 10.6- and 13.2-fold against RSV-B, respectively, 1 month postvaccination and remained 8.9–10.0-fold over prevaccination at day 43 postdelivery; (2) nAb titers were consistently higher compared to placebo recipients; (3) placental transfer ratios for anti-RSVPreF3 antibodies at birth were 1.62 and 1.90, respectively, and (4) nAb levels in infants were highest at birth and declined through day 181 postbirth. Conclusions RSVPreF3 maternal vaccination had an acceptable safety risk profile and induced robust RSV-specific immune responses with successful antibody transfer to their newborns. Clinical Trials Registration NCT04126213. [ABSTRACT FROM AUTHOR]

Introduction: Placental transfer of maternal antibodies is essential for neonatal immunity over the first months of life. In the setting of maternal HIV infection, HIV-exposed uninfected (HEU) infants are at higher risk of developing severe infections, including active tuberculosis (TB). Given our emerging appreciation for the potential role of antibodies in the control of Mycobacterium tuberculosis (Mtb), the bacteria that causes TB, here we aimed to determine whether maternal HIV status altered the quality of Mtb-specific placental antibody transfer. Methods: Antigen-specific antibody systems serology was performed to comprehensively characterize the Mtb-specific humoral immune response in maternal and umbilical cord blood from HIV infected and uninfected pregnant people in Uganda. Results: Significant differences were noted in overall antibody profiles in HIV positive and negative maternal plasma, resulting in heterogeneous transfer of Mtb-specific antibodies. Altered antibody transfer in HIV infected dyads was associated with impaired binding to IgG Fc-receptors, which was directly linked to HIV viral loads and CD4 counts. Conclusions: These results highlight the importance of maternal HIV status on antibody transfer, providing clues related to alterations in transferred maternal immunity that may render HEU infants more vulnerable to TB than their HIVunexposed peers. [ABSTRACT FROM AUTHOR]

Per- and polyfluoroalkyl substances (PFASs) are important and ubiquitous environmental contaminants worldwide. These novel contaminants can enter human bodies via various pathways, subsequently posing risks to the ecosystem and human health. The exposure of pregnant women to PFASs might pose risks to the health of mothers and the growth and development of fetuses. However, little information is available about the placental transfer of PFASs from mothers to fetuses and the related mechanisms through model simulation. In the present study, based upon a review of previously published literature, we initially summarized the exposure pathways of PFASs in pregnant women, factors affecting the efficiency of placental transfer, and mechanisms associated with placental transfer; outlined simulation analysis approaches using molecular docking and machine learning to reveal the mechanisms of placental transfer; and finally highlighted future research emphases that need to be focused on. Consequently, it was notable that the binding of PFASs to proteins during placental transfer could be simulated by molecular docking and that the placental transfer efficiency of PFASs could also be predicted by machine learning. Therefore, future research on the maternal–fetal transfer mechanisms of PFASs with the benefit of simulation analysis approaches is warranted to provide a scientific basis for the health effects of PFASs on newborns. [ABSTRACT FROM AUTHOR]

The protection of the neonate against pathogens depends largely on the antibodies transferred placentally from the mother; for this reason, maternal vaccination against emerging viruses, such as SARS-CoV-2, is of vital importance. Knowing some of the immunogenic factors that could alter the placental transfer of antibodies could aid in understanding the immune response and neonatal protection after maternal vaccination. In this study, we analyzed the efficiency of the placental transfer of binding and neutralizing antibodies, as well as some factors that could alter the passive immune response, such as the trimester of gestation at the time of immunization, the number of doses received by the mother and the type of vaccine. Binding IgG antibodies were detected by ELISA, and the detection of neutralizing antibodies was carried out using flow cytometry. Our results show efficient transfer rates (>1), which are higher when maternal vaccination occurs during the third trimester of gestation. Antibodies are detectable in mothers and their neonates after 12 months of maternal immunization, suggesting than the vaccination against COVID-19 before and during pregnancy in the Mexican population induces a lasting neutralizing response in mothers and their newborns.

IntroductionPlacental transfer of maternal antibodies is essential for neonatal immunity over the first months of life. In the setting of maternal HIV infection, HIV-exposed uninfected (HEU) infants are at higher risk of developing severe infections, including active tuberculosis (TB). Given our emerging appreciation for the potential role of antibodies in the control of Mycobacterium tuberculosis (Mtb), the bacteria that causes TB, here we aimed to determine whether maternal HIV status altered the quality of Mtb-specific placental antibody transfer.MethodsAntigen-specific antibody systems serology was performed to comprehensively characterize the Mtb-specific humoral immune response in maternal and umbilical cord blood from HIV infected and uninfected pregnant people in Uganda.ResultsSignificant differences were noted in overall antibody profiles in HIV positive and negative maternal plasma, resulting in heterogeneous transfer of Mtb-specific antibodies. Altered antibody transfer in HIV infected dyads was associated with impaired binding to IgG Fc-receptors, which was directly linked to HIV viral loads and CD4 counts.ConclusionsThese results highlight the importance of maternal HIV status on antibody transfer, providing clues related to alterations in transferred maternal immunity that may render HEU infants more vulnerable to TB than their HIV-unexposed peers.

ABSTRACT Transplacental transfer of maternal antibodies provides the fetus and newborn with passive protection against infectious diseases. While the role of the highly conserved neonatal Fc receptor (FcRn) in transfer of IgG in mammals is undisputed, recent reports have suggested that a second receptor may contribute to transport in humans. We report poor transfer efficiency of plant-expressed recombinant HIV-specific antibodies, including engineered variants with high FcRn affinity, following subcutaneous infusion into rhesus macaques close to parturition. Unexpectedly, unlike those derived from mammalian tissue culture, plant-derived antibodies were essentially unable to cross macaque placentas. This defect was associated with poor Fcγ receptor binding and altered Fc glycans and was not recapitulated in mice. These results suggest that maternal-fetal transfer of IgG across the three-layer primate placenta may require a second receptor and suggest a means of providing maternal antibody treatments during pregnancy while avoiding fetal harm. IMPORTANCE This study compared the ability of several human HIV envelope-directed monoclonal antibodies produced in plants with the same antibodies produced in mammalian cells for their ability to cross monkey and mouse placentas. We found that the two types of antibodies have comparable transfer efficiencies in mice, but they are differentially transferred across macaque placentas, consistent with a two-receptor IgG transport model in primates. Importantly, plant-produced monoclonal antibodies have excellent binding characteristics for human FcRn receptors, permitting desirable pharmacokinetics in humans. The lack of efficient transfer across the primate placenta suggests that therapeutic plant-based antibody treatments against autoimmune diseases and cancer could be provided to the mother while avoiding transfer and preventing harm to the fetus.

Pregnant women who receive the COVID-19 vaccine develop anti-SARS-CoV-2 antibodies, which can be transferred to the fetus. However, the effectiveness of placental transfer has not been evaluated in twin pregnancy, especially in cases vaccinated with heterologous CoronaVac (Sinovac)—ChAdOx1 (Oxford-AstraZeneca) regimen, which was commonly used in many countries. Case: A 34-year-old Thai woman with a twin pregnancy attended our antenatal care clinic at 21 + 2 weeks of gestation and requested COVID-19 vaccination. Her medical history and physical examination were unremarkable. She had not received COVID-19 vaccination before. Ultrasound screening for fetal anomaly revealed a dichorion diamnion twin pregnancy. Both twins showed no structural anomaly. She received the CoronaVac vaccine at 21 + 2 weeks of gestation without serious side effects and the ChAdOx1 vaccine at 24 + 2 weeks of gestation. Cesarean delivery was performed at 36 + 5 weeks of gestation, giving birth to the two healthy babies. The levels of anti-spike protein IgG levels (BAU/mL) in maternal blood just before delivery and umbilical cord blood of the two newborns were 313.349, 678.219, and 874.853, respectively. The levels of % inhibition (wild-type and delta) in the two newborns were also higher than those in the mother. In conclusion, heterologous CoronaVac-ChAdOx1-S vaccination in a twin pregnancy could effectively provide protective immunity to both twin newborns. The antibody levels in both were approximately two times higher than those in the mothers. This case report may serve as a reference in counseling couples with a twin pregnancy, while the studies on placental transfer of vaccine-derived antibodies in twin pregnancy are currently not available, especially in countries experiencing a vaccine shortage or unavailability of mRNA vaccines. [ABSTRACT FROM AUTHOR]

Background and Aims Evidence on the safety of newer biologics during pregnancy is limited. We aimed to assess the safety of ustekinumab and vedolizumab treatment during gestation on pregnancy and infant outcome. Furthermore, we evaluated the placental transfer of these agents. Methods We performed a prospective, multicentre, observational study in consecutive women with inflammatory bowel disease exposed to ustekinumab or vedolizumab 2 months prior to conception or during pregnancy. Pregnancy, neonatal, and infant outcomes were evaluated and compared with the anti-tumour necrosis factor [TNF]-exposed control group. Drug levels were assessed in maternal and cord blood at delivery. Results We included 54 and 39 pregnancies exposed to ustekinumab and vedolizumab, respectively. In the ustekinumab group, 43 [79.9%] resulted in live births, and 11 [20.4%] led to spontaneous abortion. Thirty-five [89.7%] pregnancies on vedolizumab ended in a live birth, two [5.1%] in spontaneous, and two [5.1%] in therapeutic abortion. No significant difference in pregnancy outcome between either the vedolizumab or the ustekinumab group and controls was observed [ p  >0.05]. Similarly, there was no negative safety signal in the postnatal outcome of exposed children regarding growth, psychomotor development, and risk of allergy/atopy or infectious complications. The median infant-to-maternal ratio of ustekinumab levels was 1.67 and it was 0.59 in vedolizumab. Conclusions Use of ustekinumab and vedolizumab in pregnancy seems to be safe, with favuorable pregnancy and postnatal infant outcomes. Placental transfer differed between these two drugs, with ustekinumab having similar and vedolizumab having inverse infant-to-maternal ratio of drug levels compared with anti-TNF preparations. [ABSTRACT FROM AUTHOR]

Abstract Background The impaired transplacental passage of IgG from mothers living with HIV to their infants could be one of the causes of the high vulnerability to infections of HIV-exposed uninfected (HEU) infants, but controversial results have been obtained in different settings. The aim of this study was to assess in 6-week old HEU and HIV-unexposed, uninfected (HUU) Malawian infants the total IgG levels, the subclasses profile and the concentrations of global anti-pneumococcal capsular polysaccharide (anti-PCP) IgG and IgG2. Methods Dried blood spots were collected from 80 infants (40 HEU, 40 HUU) and antibodies concentrations determined by nephelometric method (total IgG and subclasses), or using ELISA (anti-PCP total IgG and IgG2). Results are expressed as median levels with IQR, while the proportions of each subclass out of the total IgG are used to describe the subclasses profile. Results At 6 weeks HEU infants had higher median levels of total IgG and IgG1 and a significantly lower level of IgG2 [0.376 (0.344–0.523) g/l vs 0.485 (0.374–0.781) g/l, p = 0.037] compared to the HUU counterparts. The IgG subclasses distribution confirmed the underrepresentation of IgG2 (IgG2 represented 5.82% of total IgG in HEU and 8.87% in HUU). The anti-PCP IgG and IgG2 levels were significantly lower in HEU infants [8.9 (5.4–15.1) mg/l vs 16.2 (9.61–25.8) mg/l in HUU, p

Establishing an immune balance between the mother and fetus during gestation is crucial, with the placenta acting as the epicenter of immune tolerance. The placental transfer of antibodies, mainly immunoglobulin G (IgG), is critical in protecting the developing fetus from infections. This review looks at how immunomodulation of antibody glycosylation occurs during placental transfer and how it affects fetal health. The passage of maternal IgG antibodies through the placental layers, including the syncytiotrophoblast, stroma, and fetal endothelium, is discussed. The effect of IgG subclass, glycosylation, concentration, maternal infections, and antigen specificity on antibody transfer efficiency is investigated. FcRn-mediated IgG transport, influenced by pH-dependent binding, is essential for placental transfer. Additionally, this review delves into the impact of glycosylation patterns on antibody functionality, considering both protective and pathological effects. Factors affecting the transfer of protective antibodies, such as maternal vaccination, are discussed along with reducing harmful antibodies. This in-depth examination of placental antibody transfer and glycosylation provides insights into improving neonatal immunity and mitigating the effects of maternal autoimmune and alloimmune conditions.

Abstract Background Little is known about the extent of drug entry into developing brain, when administered to pregnant and lactating women. Lithium is commonly prescribed for bipolar disorder. Here we studied transfer of lithium given to dams, into blood, brain and cerebrospinal fluid (CSF) in embryonic and postnatal animals as well as adults. Methods Lithium chloride in a clinically relevant dose (3.2 mg/kg body weight) was injected intraperitoneally into pregnant (E15–18) and lactating dams (birth-P16/17) or directly into postnatal pups (P0–P16/17). Acute treatment involved a single injection; long-term treatment involved twice daily injections for the duration of the experiment. Following terminal anaesthesia blood plasma, CSF and brains were collected. Lithium levels and brain distribution were measured using Laser Ablation Inductively Coupled Plasma-Mass Spectrometry and total lithium levels were confirmed by Inductively Coupled Plasma-Mass Spectrometry. Results Lithium was detected in blood, CSF and brain of all fetal and postnatal pups following lithium treatment of dams. Its concentration in pups’ blood was consistently below that in maternal blood (30–35%) indicating significant protection by the placenta and breast tissue. However, much of the lithium that reached the fetus entered its brain. Levels of lithium in plasma fluctuated in different treatment groups but its concentration in CSF was stable at all ages, in agreement with known stable levels of endogenous ions in CSF. There was no significant increase of lithium transfer into CSF following application of Na+/K+ ATPase inhibitor (digoxin) in vivo, indicating that lithium transfer across choroid plexus epithelium is not likely to be via the Na+/K+ ATPase mechanism, at least early in development. Comparison with passive permeability markers suggested that in acute experiments lithium permeability was less than expected for diffusion but similar in long-term experiments at P2. Conclusions Information obtained on the distribution of lithium in developing brain provides a basis for studying possible deleterious effects on brain development and behaviour in offspring of mothers undergoing lithium therapy.

OBJECTIVE: To probe into the placental permeability of escitalopram by human placental extracorporeal circulation perfusion model. METHODS: Healthy and full-term human placentas that had just been delivered were selected, the placental extracorporeal circulation perfusion model was established and circularly perfused for 3 h. During this period, samples were taken from the maternal pool and the fetal pool, and the pH, PO2, β-human chorionic gonadotropin, glucose consumption, lactate production, fluid loss from the fetal pool, the concentrations of positive controls of antipyrine and escitalopram were detected to assess the placental transmission rates. RESULTS: In this study, 158 human placental extracorporeal circulation perfusion models were performed, and 15 cases met the criteria for successful model establishment. After 3 h of circulation perfusion, the placental permeation rate of escitalopram was ( 9. 09 ± 2. 80)% and the relative permeation rate was ( 23. 35 ± 4. 37 )%. CONCLUSIONS: Escitalopram can penetrate the placenta in small dose and lead to fetal exposure to escitalopram. [ABSTRACT FROM AUTHOR]

Introduction: Pregnancy requires women to provide calcium to foetus in amounts that may exceed their daily intake. C-Reactive Protein (CRP) is a susceptible marker of systemic inflammation. Parathyroid hormone (PTH) regulates foeto-placental mineral homeostasis and skeletal development and stimulates placental calcium transfer. The increase in calcitonin and calcitriol levels are significant in the transport of maternal calcium to the foetus and in the anticipation, and revival of maternal bone loss. These changes have direct implications on calcium metabolism and cause decreased albumin level, inflammation, increase in extracellular fluid volume, increase in renal function, and placental calcium transfer. Aim: To assess the serum levels of CRP, calcitonin, and PTH in the first, second, and third trimester of pregnancy and also to compare these parameters with non pregnant women. Materials and Methods: The present case-control study was conducted in the Department of Biochemistry of Nootan Medical College and Research Centre, Visnagar, Gujarat, from June 2021 to October 2021. A total of 150 subjects (75 age and sexmatched apparently healthy well-nourished non pregnant females, and 75 pregnant females) were included. The CRP, PTH, and calcitonin were measured. Statistical analysis was performed using Independent t-test, and Pearson’s correlation coefficient (r). Results: Mean age of participants in case group was 32.16±10.97 (mean±SD). The mean age of control was 30.54±6.63. Serum CRP level of cases was significantly higher 3.2±2.2 than the level in controls 2.3±1.8 (p=0.003). Serum PTH level of cases 31.6±10.4 was significantly lower (p=0.0012) than the level in controls 45.9±9.8. Serum calcitonin level of cases 281±143 was significantly higher (p<0.001) than the level in controls 103±46. Conclusion: There was a significant increase in serum CRP level and serum calcitonin level in cases as compared with controls, while there is decrease in serum PTH levels between these two groups. [ABSTRACT FROM AUTHOR]

Introduction: Pregnancy requires women to provide calcium to foetus in amounts that may exceed their daily intake. C-Reactive Protein (CRP) is a susceptible marker of systemic inflammation. Parathyroid hormone (PTH) regulates foeto-placental mineral homeostasis and skeletal development and stimulates placental calcium transfer. The increase in calcitonin and calcitriol levels are significant in the transport of maternal calcium to the foetus and in the anticipation, and revival of maternal bone loss. These changes have direct implications on calcium metabolism and cause decreased albumin level, inflammation, increase in extracellular fluid volume, increase in renal function, and placental calcium transfer. Aim: To assess the serum levels of CRP, calcitonin, and PTH in the first, second, and third trimester of pregnancy and also to compare these parameters with non pregnant women. Materials and Methods: The present case-control study was conducted in the Department of Biochemistry of Nootan Medical College and Research Centre, Visnagar, Gujarat, from June 2021 to October 2021. A total of 150 subjects (75 age and sex-matched apparently healthy well-nourished non pregnant females, and 75 pregnant females) were included. The CRP, PTH, and calcitonin were measured. Statistical analysis was performed using Independent t-test, and Pearson’s correlation coefficient (r). Results: Mean age of participants in case group was 32.16±10.97 (mean±SD). The mean age of control was 30.54±6.63. Serum CRP level of cases was significantly higher 3.2±2.2 than the level in controls 2.3±1.8 (p=0.003). Serum PTH level of cases 31.6±10.4 was significantly lower (p=0.0012) than the level in controls 45.9±9.8. Serum calcitonin level of cases 281±143 was significantly higher (p

Per- and polyfluoroalkyl substances (PFASs) are important and ubiquitous environmental contaminants worldwide. These novel contaminants can enter human bodies via various pathways, subsequently posing risks to the ecosystem and human health. The exposure of pregnant women to PFASs might pose risks to the health of mothers and the growth and development of fetuses. However, little information is available about the placental transfer of PFASs from mothers to fetuses and the related mechanisms through model simulation. In the present study, based upon a review of previously published literature, we initially summarized the exposure pathways of PFASs in pregnant women, factors affecting the efficiency of placental transfer, and mechanisms associated with placental transfer; outlined simulation analysis approaches using molecular docking and machine learning to reveal the mechanisms of placental transfer; and finally highlighted future research emphases that need to be focused on. Consequently, it was notable that the binding of PFASs to proteins during placental transfer could be simulated by molecular docking and that the placental transfer efficiency of PFASs could also be predicted by machine learning. Therefore, future research on the maternal–fetal transfer mechanisms of PFASs with the benefit of simulation analysis approaches is warranted to provide a scientific basis for the health effects of PFASs on newborns.

• First real-world serology study on recombinant pertussis vaccination in pregnancy. • Recombinant pertussis vaccine induces high placental pertussis antibody transfer. • Recombinant pertussis vaccination in pregnancy is safe. This study investigates placental antibody transfer following recombinant pertussis vaccination in pregnancy in a real-world setting. This postmarketing observational study recruited pregnant women vaccinated with monovalent recombinant acellular pertussis (aP) vaccine (aP gen ; n = 199) or combined to tetanus-diphtheria (TdaP gen ; n = 200), or Td-vaccine only (n = 54). Pregnancy, delivery, and neonatal outcomes were assessed. Cord blood was collected postdelivery and pertussis toxin (PT)-IgG, filamentous hemagglutinin (FHA)-IgG, and PT-neutralizing antibodies (PT-Nab) were assessed. No adverse pregnancy, delivery, or neonatal outcomes attributed to aP gen , TdaP gen , or Td vaccination were reported. High anti-PT antibody levels were detected in cord samples from women vaccinated with aP gen (geometric mean concentration [GMC] PT-IgG 206.1 IU/ml, 95% confidence intervals [CI]: 164.3-258.6; geometric mean titer [GMT] PT-Nab 105.3 IU/ml, 95% CI: 81.7-135.8) or TdaP gen (GMC PT-IgG 153.1 IU/ml, 95% CI: 129.1-181.5; GMT PT-Nab 81.5 IU/ml, 95% CI: 66.4-100.0). In the Td-only group, anti-PT antibodies were low (GMC PT-IgG 6.5 IU/ml, 95% CI: 4.9-8.8; GMT PT-Nab 3.8 IU/ml, 95% CI: 2.8-5.1). The same was found for FHA-IgG. Recombinant pertussis vaccination at <27 or 27-36 weeks gestation induced similar cord pertussis antibody levels. This first real-world study confirms that recombinant pertussis vaccination in the second or third trimester of pregnancy results in high levels of passive immunity in infants. Thai Clinical Trial Registry: TCTR20200528006. [ABSTRACT FROM AUTHOR]

Nutrition and lifestyle have a great impact on reproduction and infertility in humans, as they are essential for certain processes such as implantation, placental growth, angiogenesis, and the transfer of nutrients from the mother to the fetus. The aim of this review is to provide the interconnection between nutrition and reproductive health through the insight of omics approaches (including metabolomics and nutrigenomics). The effect of various macronutrients, micronutrients, and some food‐associated components on male and female reproduction was discussed. Recent research work was collected through database search from 2010 to 2020 to identify eligible studies. Alterations of metabolic pathways in pregnant women were deliberated with an emphasis on different strategies of lifestyle and dietary interventions. Several nutritional methods, which are important for embryonic and child neurological development, nutritional supplements to lactation, and improved gestational length along with birth weight have been emphasized. Considerable advances in omics strategies show potential technological development for improving human reproductive health. [ABSTRACT FROM AUTHOR]

At least 80% of pregnant woman in Europe use at least one medication during their pregnancy. The majority of these drugs are prescribed off-label. A better understanding of drug transport and effects in the placenta can provide an improved pharmacological basis to rationalize drug and dose selection for prescription. Here we provide a narrative review of studies that used the ex vivo placenta perfusion model to study placental drug transport and vascular effects of pharmaceuticals. For studies on placental transfer, we found that the methodology used varied substantially between studies as well as the way in which data was reported. Across the different therapeutic groups, ex vivo measurements of transfer generally corresponded well to in vivo findings. Still, further standardization of the perfusion technique would facilitate a broader use of perfusion data, e.g. in the context of quantitative systems pharmacology models as has been explored in recent years. Only few studies investigated the effects of drugs on the vascular tone using the ex vivo dual-side perfusion model. The model was particularly applied to study vasodilatory effects of pharmaceuticals in the fetoplacental circulation. In conclusion, the ex vivo dually perfused human cotyledon provides a relevant system to gain insights in placental drug disposition and study effects on the fetoplacental vasculature. [ABSTRACT FROM AUTHOR]

Background: The impaired transplacental passage of IgG from mothers living with HIV to their infants could be one of the causes of the high vulnerability to infections of HIV-exposed uninfected (HEU) infants, but controversial results have been obtained in different settings. The aim of this study was to assess in 6-week old HEU and HIV-unexposed, uninfected (HUU) Malawian infants the total IgG levels, the subclasses profile and the concentrations of global anti-pneumococcal capsular polysaccharide (anti-PCP) IgG and IgG2.Methods: Dried blood spots were collected from 80 infants (40 HEU, 40 HUU) and antibodies concentrations determined by nephelometric method (total IgG and subclasses), or using ELISA (anti-PCP total IgG and IgG2). Results are expressed as median levels with IQR, while the proportions of each subclass out of the total IgG are used to describe the subclasses profile.Results: At 6 weeks HEU infants had higher median levels of total IgG and IgG1 and a significantly lower level of IgG2 [0.376 (0.344-0.523) g/l vs 0.485 (0.374-0.781) g/l, p = 0.037] compared to the HUU counterparts. The IgG subclasses distribution confirmed the underrepresentation of IgG2 (IgG2 represented 5.82% of total IgG in HEU and 8.87% in HUU). The anti-PCP IgG and IgG2 levels were significantly lower in HEU infants [8.9 (5.4-15.1) mg/l vs 16.2 (9.61-25.8) mg/l in HUU, p < 0.001, and 2.69 (1.90-4.29) mg/l vs 4.47 (2.96-5.71) mg/l in HUU, p = 0.001, respectively].Conclusion: Compared to HUU infants, HEU infants have IgG abnormalities mainly represented by low IgG2 levels, suggesting that despite maternal antiretroviral therapy, the mechanisms of IgG transplacental passage continue to be impaired in women living with HIV. HEU infants also showed a significantly lower level of specific anti-PCP IgG, possibly favouring a high vulnerability to S. pneumoniae infection at an age when protection is mostly depending on maternal IgG. [ABSTRACT FROM AUTHOR]

Aim: No study has evaluated the betamethasone pharmacokinetics in twin pregnancies according to chorionicity. This study aimed to describe and compare the betamethasone pharmacokinetic parameters in singleton and dichorionic (DC) and monochorionic twin pregnancies in the third trimester of pregnancy. Methods: Twenty‐six pregnant women received 2 intramuscular doses of 6 mg of betamethasone sodium phosphate plus 6 mg betamethasone acetate due to preterm labour. Serial blood samples were collected for 24 hours after the first intramuscular dose of betamethasone esters. Betamethasone plasma concentrations were quantified using a validated liquid chromatography–tandem mass spectrometry analytical method, and the pharmacokinetic parameters were obtained employing a noncompartmental model. Preliminary data on the betamethasone placental transfer are also presented. Results: The geometric mean (95% confidence interval) of AUC0‐∞ 645.1 (504.3–825.2) vs. 409.8 (311.2–539.6) ng.h/mL and CL/F 17.70 (13.84–22.65) vs. 27.87 (21.17–36.69) were significantly different, respectively, in singleton pregnancies when compared to DC twins. Conclusion: Data from this study suggest that the presence of 2 foetoplacental units may increase the betamethasone metabolism by hepatic CYP3A4 and/or placental 11β‐HSD2 enzymes. Pharmacokinetic–pharmacodynamic clinical studies are needed to investigate whether these betamethasone pharmacokinetic changes have clinical repercussions for the newborns and require dose adjustment in DC twin pregnancies. [ABSTRACT FROM AUTHOR]

The overwhelming success of tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia (CML) patients has opened a discussion among medical practitioners and the lay public on the real possibility of pregnancy and conception in females and males with CML. In the past 10 years this subject has acquired growing interest in the scientific community and specific knowledge has been obtained "from bench to bedside". Embryological, pharmacological, and pathophysiological studies have merged with worldwide patient databases to provide a roadmap to a successful pregnancy and birth in CML patients. Male conception does not seem to be affected by TKI therapy, since this class of drugs is neither genotoxic nor mutagenic, however, caution should be used specially with newer drugs for which little or no data are available. In contrast, female patients should avoid TKI therapy specifically during the embryonic stage of organogenesis (5–12 weeks) because TKIs can be teratogenic. In the last 15 years, 41 pregnancies have been followed in our center. A total of 11 male conceptions and 30 female pregnancies are described. TKI treatment was generally terminated as soon as the pregnancy was discovered (3–5 weeks), to avoid exposure during embryonic period and to reduce the risk of needing treatment in the first trimester. Eleven pregnancies were treated with interferon, imatinib or nilotinib during gestation. Nilotinib plasma levels in cord blood and maternal blood at delivery were studied in 2 patients and reduced or absent placental crossing of nilotinib was observed. All of the patients were managed by a multidisciplinary team of physicians with obligatory hematological and obgyn consultations. This work provides an update on the state of the art and detailed description of pregnancy management and outcomes in CML patients. [ABSTRACT FROM AUTHOR]

Manganese (Mn) as well as iron (Fe) are essential trace elements (TE) important for the maintenance of physiological functions including fetal development. However, in the case of Mn, evidence suggests that excess levels of intrauterine Mn are associated with adverse pregnancy outcomes. Although Mn is known to cross the placenta, the fundamentals of Mn transfer kinetics and mechanisms are largely unknown. Moreover, exposure to combinations of TEs should be considered in mechanistic transfer studies, in particular for TEs expected to share similar transfer pathways. Here, we performed a mechanistic in vitro study on the placental transfer of Mn across a BeWo b30 trophoblast layer. Our data revealed distinct differences in the placental transfer of Mn and Fe. While placental permeability to Fe showed a clear inverse dose-dependency, Mn transfer was largely independent of the applied doses. Concurrent exposure of Mn and Fe revealed transfer interactions of Fe and Mn, indicating that they share common transfer mechanisms. In general, mRNA and protein expression of discussed transporters like DMT1, TfR, or FPN were only marginally altered in BeWo cells despite the different exposure scenarios highlighting that Mn transfer across the trophoblast layer likely involves a combination of active and passive transport processes. [ABSTRACT FROM AUTHOR]

Mammals can obtain taurine from food and synthesize it from sulfur-containing amino acids. Mammalian fetuses and infants have little ability to synthesize taurine. Therefore, they are dependent on taurine given from mothers either via the placenta or via breast milk. Many lines of evidence demonstrate that maternally derived taurine is essential for offspring development, shaping various traits in adults. Various environmental factors, including maternal obesity, preeclampsia, and undernutrition, can affect the efficacy of taurine transfer via either the placenta or breast milk. Thus, maternally derived taurine during the perinatal period can influence the offspring's development and even determine health and disease later in life. In this review, I will discuss the biological function of taurine during development and the regulatory mechanisms of taurine transport from mother to offspring. I also refer to the possible environmental factors affecting taurine functions in mother-offspring bonding during perinatal periods. The possible functions of taurine as a determinant of gut microbiota and in the context of the Developmental Origins of Health and Disease (DOHaD) hypothesis will also be discussed. [ABSTRACT FROM AUTHOR]

Background: Little is known about the extent of drug entry into developing brain, when administered to pregnant and lactating women. Lithium is commonly prescribed for bipolar disorder. Here we studied transfer of lithium given to dams, into blood, brain and cerebrospinal fluid (CSF) in embryonic and postnatal animals as well as adults. Methods: Lithium chloride in a clinically relevant dose (3.2 mg/kg body weight) was injected intraperitoneally into pregnant (E15–18) and lactating dams (birth-P16/17) or directly into postnatal pups (P0–P16/17). Acute treatment involved a single injection; long-term treatment involved twice daily injections for the duration of the experiment. Following terminal anaesthesia blood plasma, CSF and brains were collected. Lithium levels and brain distribution were measured using Laser Ablation Inductively Coupled Plasma-Mass Spectrometry and total lithium levels were confirmed by Inductively Coupled Plasma-Mass Spectrometry. Results: Lithium was detected in blood, CSF and brain of all fetal and postnatal pups following lithium treatment of dams. Its concentration in pups' blood was consistently below that in maternal blood (30–35%) indicating significant protection by the placenta and breast tissue. However, much of the lithium that reached the fetus entered its brain. Levels of lithium in plasma fluctuated in different treatment groups but its concentration in CSF was stable at all ages, in agreement with known stable levels of endogenous ions in CSF. There was no significant increase of lithium transfer into CSF following application of Na+/K+ ATPase inhibitor (digoxin) in vivo, indicating that lithium transfer across choroid plexus epithelium is not likely to be via the Na+/K+ ATPase mechanism, at least early in development. Comparison with passive permeability markers suggested that in acute experiments lithium permeability was less than expected for diffusion but similar in long-term experiments at P2. Conclusions: Information obtained on the distribution of lithium in developing brain provides a basis for studying possible deleterious effects on brain development and behaviour in offspring of mothers undergoing lithium therapy. [ABSTRACT FROM AUTHOR]

Background: Calcium and magnesium are one of the most important micronutrients for fetal development. Environmental pollutants such as excess fluoride can hamper the action of calcium and magnesium, resulting in a bad outcome of pregnancy. Aim: We aimed to find out the effect of fluoride on the uteroplacental transfer of calcium and magnesium and their role of these minerals as a causative factor of congenital anomalies in newborns. Methods: Thirty newborns with congenital anomalies were included in Group I, and thirty healthy newborns were included in Group II. Cord blood fluoride was estimated by ion-selective electrode, whereas calcium and magnesium were estimated by the autoanalyzer. Unpaired “t” test and Pearson's correlation test were applied for the statistical analysis. Results: Serum fluoride levels were significantly raised, and serum calcium levels and serum magnesium levels were statistically significantly decreased in newborns with congenital anomalies as compared to newborns without congenital anomalies (P = 0.000). Serum fluoride levels showed a positive correlation with serum calcium in Group II, which got inverted in Group I. Both the results were statistically significant. Serum fluoride levels showed a positive correlation with serum magnesium levels in Group II, which got inverted in Group I. Both the results were statistically insignificant. Conclusion: Hypokalcemia and hypomagnesemia can affect fetal development. Environmental pollution due to fluorosis emerges as a factor as fluoride has a direct influence over calcium and magnesium absorption and transfer through the placenta to the developing fetus. Prophylactic measures have to be taken to counter the effect of fluorides on calcium and magnesium for the proper development of the growing fetus.

Summary: Influenza is an important cause of illness and morbidity for infants. Seasonal influenza vaccination during pregnancy aims to provide protection to mothers, but it can also provide immunity to infants. The precise influence of maternal vaccination on immunity in infants and how vaccine-elicited antibodies provide protection in some but not all infants is incompletely understood. We comprehensively profiled the transfer of functional antibodies and defined humoral factors contributing to immunity against influenza in a clinical trial of maternal influenza vaccination. Influenza-specific antibody subclass levels, Fc ɣ receptor (FCGR) binding levels, and antibody-dependent innate immune functions were all profiled in the mothers during pregnancy and at birth, as well as in cord blood. Vaccination increased influenza-specific antibody levels, antibody binding to FCGR, and specific antibody-dependent innate immune functions in both maternal and cord blood, with FCGR binding most enhanced via vaccination. Influenza-specific FCGR binding levels were lower in cord blood of infants who subsequently developed influenza infection. Collectively these data suggest that in addition to increased antibody amounts, the selective transfer of FCGR-binding antibodies contributes to the protective immune response in infants against influenza.

Pregnant women who receive the COVID-19 vaccine develop anti-SARS-CoV-2 antibodies, which can be transferred to the fetus. However, the effectiveness of placental transfer has not been evaluated in twin pregnancy, especially in cases vaccinated with heterologous CoronaVac (Sinovac)—ChAdOx1 (Oxford-AstraZeneca) regimen, which was commonly used in many countries. Case: A 34-year-old Thai woman with a twin pregnancy attended our antenatal care clinic at 21 + 2 weeks of gestation and requested COVID-19 vaccination. Her medical history and physical examination were unremarkable. She had not received COVID-19 vaccination before. Ultrasound screening for fetal anomaly revealed a dichorion diamnion twin pregnancy. Both twins showed no structural anomaly. She received the CoronaVac vaccine at 21 + 2 weeks of gestation without serious side effects and the ChAdOx1 vaccine at 24 + 2 weeks of gestation. Cesarean delivery was performed at 36 + 5 weeks of gestation, giving birth to the two healthy babies. The levels of anti-spike protein IgG levels (BAU/mL) in maternal blood just before delivery and umbilical cord blood of the two newborns were 313.349, 678.219, and 874.853, respectively. The levels of % inhibition (wild-type and delta) in the two newborns were also higher than those in the mother. In conclusion, heterologous CoronaVac-ChAdOx1-S vaccination in a twin pregnancy could effectively provide protective immunity to both twin newborns. The antibody levels in both were approximately two times higher than those in the mothers. This case report may serve as a reference in counseling couples with a twin pregnancy, while the studies on placental transfer of vaccine-derived antibodies in twin pregnancy are currently not available, especially in countries experiencing a vaccine shortage or unavailability of mRNA vaccines.

A maternal Group B Streptococcus (GBS) six‐valent polysaccharide conjugate vaccine (GBS6) is being developed to protect neonates and infants up to 3 months of age through passive transfer of antibodies from the mother to the infant. Fertility and developmental toxicity studies were conducted in female Sprague Dawley rats and New Zealand White rabbits with GBS6 (20 μg capsular polysaccharide/serotype formulated with or without AlPO4, the highest clinical dose). Females were administered the full human dose of the GBS6 formulation intramuscularly twice prior to mating and twice during gestation, to ensure that high antibody levels were maintained throughout gestation and lactation. Approximately, half of the rats and rabbits were evaluated at the end of gestation, and the remainder were evaluated at the end of lactation. Maternal blood for GBS6 serology, to measure antibody titers to the GBS6 antigens, was collected prior to the first dose, prior to mating, and at each necropsy. Blood for serology was also collected from offspring at the end of gestation and lactation. In both species, there was no evidence of vaccine‐related effects on fertility, embryo‐fetal development, or postnatal development of the offspring, supporting regulatory guidance that single‐species evaluation would have been sufficient. Functional serum antibodies to all six serotypes in the vaccine were confirmed in maternal animals and functional serum antibodies to one or more of the six serotypes was also confirmed in some rat offspring and most of the rabbit offspring. The results of these studies supported the safety of GBS6 vaccine administration to pregnant women. [ABSTRACT FROM AUTHOR]

The aim was to characterize placental transfer of some congeners of polychlorinated biphenyls (PCBs) and to relate human in utero exposure to these pollutants to their physicochemical properties. We included into the study 1134 births during the period 2002-2003 from two highly PCB contaminated districts in eastern Slovakia. Concentrations of 15 PCB congeners (IUPAC No. 28, 52, 101, 123(+149), 118, 114, 153, 105, 138(+163), 167, 156(+171), 157, 180, 170, and 189) in umbilical cord (C) and maternal serum (M) were determined. The C/M ratios were significantly related, either positively or inversely depending on parameter, to the logarithm of partition coefficient octanol-water (KOW), to fusion enthalpy at the melting point, molecular weight, water solubility, total surface area of the molecule, solvent accessible surface area, melting point, molar volume, and molecular electronegativity distance vector. We found an inverse association between logKOW and lipid adjusted logC/M (const=1.078, b1=-0.179, p

Little is known about placental drug transfer and fetal pharmacokinetics despite increasing drug use in pregnant women. While physiologically based pharmacokinetic (PBPK) models can help in some cases to shed light on this knowledge gap, adequate parameterization of placental drug transfer remains challenging. A novel in silico model with seven compartments representing the ex vivo cotyledon perfusion assay was developed and used to describe placental transfer and fetal pharmacokinetics of acetaminophen. Unknown parameters were optimized using observed data. Thereafter, values of relevant model parameters were copied to a maternal-fetal PBPK model and acetaminophen pharmacokinetics were predicted at delivery after oral administration of 1,000 mg. Predictions in the umbilical vein were evaluated with data from two clinical studies. Simulations from the in silico cotyledon perfusion model indicated that acetaminophen accumulates in the trophoblasts; simulated steady state concentrations in the trophoblasts were 4.31-fold higher than those in the perfusate. The whole-body PBPK model predicted umbilical vein concentrations with a mean prediction error of 24.7%. Of the 62 concentration values reported in the clinical studies, 50 values (81%) were predicted within a 2-fold error range. In conclusion, this study presents a novel in silico cotyledon perfusion model that is structurally congruent with the placenta implemented in our maternal-fetal PBPK model. This allows transferring parameters from the former model into our PBPK model for mechanistically exploring whole-body pharmacokinetics and concentration-effect relationships in the placental tissue. Further studies should investigate acetaminophen accumulation and metabolism in the placenta as the former might potentially affect placental prostaglandin synthesis and subsequent fetal exposure.

Prenatal exposure to perfluoroalkyl substances (PFAS), bisphenol A (BPA), lead (Pb), total mercury (THg), and methylmercury (MeHg) can affect fetal development. Factors influencing placental transfer rate of these toxins are poorly investigated. Whether prenatal exposure to pollutants has an effect on birth weight is incompletely understood. We therefore aimed (1) to determine placental transfer rates of PFAS, BPA, Pb, THg, and MeHg, (2) to analyze relationships between fetal exposure and birth outcome and (3) to analyze gene variants as mediators of placental transfer rates and birth outcome. Two hundred healthy pregnant women and their newborns participated in the study. BPA, 16 PFAS, THg, MeHg, and Pb were determined using HPLCMS/MS (BPA, PFAS), HPLC-CV-ICPMS (MeHg), CV-AFS (THg), and GF-AAS (Pb). Questionnaires and medical records were used to survey exposure sources and birth outcome. 20 single nucleotide polymorphisms and two deletion polymorphisms were determined by real-time PCR from both maternal and newborn blood. Genotype-phenotype associations were analyzed by categorical regression and logistic regression analysis. Specific gene variants were associated with altered placental transfer of PFAS (ALAD Lys59Asn, ABCG2 Gln141Lys), THg (UGT Tyr85Asp, GSTT1del, ABCC1 rs246221) and Pb (GSTP1 Ala114Val). A certain combination of three gene polymorphisms (ABCC1 rs246221, GCLM rs41303970, HFE His63Asp) was over-represented in newborns small for gestational age. 36% of Austrian and 75% of Slovakian mothers had levels exceeding the HBM guidance value I (2 μg/L) of the German HBM Commission for PFOA. 13% of newborns and 39% of women had Ery-Pb levels above 24 μg/kg, an approximation for the BMDL01 of 12 μg/L set by the European Food Safety Authority (EFSA). Our findings point to the need to minimize perinatal exposures to protect fetal health, especially those genetically predisposed to increased transplacental exposure.

Obstetrical complications, often referred to as the "great obstetrical syndromes," are among the most common global causes of mortality and morbidity in young women and their infants. However, treatments for these syndromes are underdeveloped compared with other fields of medicine and are urgently needed. This current paucity of treatments for obstetrical complications is a reflection of the challenges of drug development in pregnancy. The appetite of pharmaceutical companies to invest in research for obstetrical syndromes is generally reduced by concerns for maternal, fetal, and infant safety, poor definition, and high-risk regulatory paths toward product approval. Notably, drug candidates require large investments for development with an unguaranteed return on investment. Furthermore, the discovery of promising drug candidates is hampered by a poor understanding of the pathophysiology of obstetrical syndromes and their uniqueness to human pregnancies. This limits translational extrapolation and de-risking strategies in preclinical studies, as available for other medical areas, compounded with limited fetal safety monitoring to capture early prenatal adverse reactions. In addition, the ethical review committees are reluctant to approve the inclusion of pregnant women in trials, and in the absence of regulatory guidance in obstetrics, clinical development programs are subject to unpredictable regulatory paths. To develop effective and safe drugs for pregnancy complications, substantial commitment, and investment in research for innovative therapies are needed in parallel with the creation of an enabling ethical, legislative, and guidance framework. Solutions are proposed to enable stakeholders to work with a common set of expectations to facilitate progress in this medical discipline. Addressing this significant unmet need to advance maternal and possibly perinatal health requires the involvement of all stakeholders and specifically patients, couples, and clinicians facing pregnancy complications in the dearth of appropriate therapies. This paper focused on the key pharmaceutical research and development challenges to achieve effective and safe treatments for obstetrical syndromes. [ABSTRACT FROM AUTHOR]

Prenatal exposure to perfluoroalkyl substances (PFAS), bisphenol A (BPA), lead (Pb), total mercury (THg), and methylmercury (MeHg) can affect fetal development. Factors influencing placental transfer rate of these toxins are poorly investigated. Whether prenatal exposure to pollutants has an effect on birth weight is incompletely understood. We therefore aimed (1) to determine placental transfer rates of PFAS, BPA, Pb, THg, and MeHg, (2) to analyze relationships between fetal exposure and birth outcome and (3) to analyze gene variants as mediators of placental transfer rates and birth outcome. Two hundred healthy pregnant women and their newborns participated in the study. BPA, 16 PFAS, THg, MeHg, and Pb were determined using HPLCMS/MS (BPA, PFAS), HPLC-CV-ICPMS (MeHg), CV-AFS (THg), and GF-AAS (Pb). Questionnaires and medical records were used to survey exposure sources and birth outcome. 20 single nucleotide polymorphisms and two deletion polymorphisms were determined by real-time PCR from both maternal and newborn blood. Genotype-phenotype associations were analyzed by categorical regression and logistic regression analysis. Specific gene variants were associated with altered placental transfer of PFAS (ALAD Lys59Asn, ABCG2 Gln141Lys), THg (UGT Tyr85Asp, GSTT1 del, ABCC1 rs246221) and Pb (GSTP1 Ala114Val). A certain combination of three gene polymorphisms (ABCC1 rs246221, GCLM rs4130 3970, HFE His63Asp) was over-represented in newborns small for gestational age. 36% of Austrian and 75% of Slovakian mothers had levels exceeding the HBM guidance value I (2 μg/L) of the German HBM Commission for PFOA. 13% of newborns and 39% of women had Ery-Pb levels above 24 μg/kg, an approximation for the BMDL01 of 12 μg/L set by the European Food Safety Authority (EFSA). Our findings point to the need to minimize perinatal exposures to protect fetal health, especially those genetically predisposed to increased transplacental exposure. [ABSTRACT FROM AUTHOR]

Introduction Lithium is an effective mood stabilizer and is widely used as a first-line treatment for bipolar disorder in the perinatal period. Several guidelines have provided clinical advice on dosing strategy (dose reduction versus stop lithium) in the peripartum period to minimize the risk of neonatal complications. An association has been observed between high neonatal lithium concentrations (> 0.64 mEq/L) and lower 1-min Apgar scores, longer hospital stays, and central nervous system and neuromuscular complications. Objectives To quantify the rate of lithium placental passage at delivery. To assess any association between plasma concentration of lithium at delivery and neonatal outcome. Methods In this retrospective observational cohort study, we included women treated with llithium at least in late pregnancy. Maternal (MB) and umbilical cord (UC) lithium blood level measurement were collected at delivery. Lithium serum concentrations were determined by means of an AVL 9180 electrolyte analyzer. The limit of quantification (LoQ) was 0.20 mEq/L and detection limit was 0.10 mEq/L. From the medical records, we extracted information on neonatal outcomes (preterm birth, birth weight, Apgar scores, pH-values, and admision to NICU) and complications categoriced by organ system: respiratory, circulatory, hematological, gastro-intestinal, metabolic, neurological, and immune system (infections). Results Umbilical cord and maternal lithium blood levels were strongly correlated: mean (SD) range UC/MR ratio 1.15 (0.24). Umbilical cord lithium levels ranged between 0.20 to 1.42 mEq/L. We observed no associations between umbilical cord lithium blood levels at delivery and neonatal outcomes. Conclusions In our study, newborns tolerated well a wide range of lithemias, between 0.20 and 1.42 mEq/L.