Prenatal Therapy Research Articles

Achondroplasia: aligning mouse model with human clinical studies shows crucial importance of immediate postnatal start of the therapy.

Achondroplasia is the most common form of human dwarfism caused by mutations in the FGFR3 receptor tyrosine kinase. Current therapy begins at two years of age and improves longitudinal growth but does not address the cranial malformations including midface hypoplasia and foramen magnum stenosis, which lead to significant otolaryngeal and neurologic compromise. A recent clinical trial found partial restoration of cranial defects with therapy starting at 3months of age, but results are still inconclusive. The benefits of achondroplasia therapy are therefore controversial, increasing skepticism among the medical community and patients. We used a mouse model of achondroplasia to test treatment protocols aligned with human studies. Early postnatal treatment (from day 1) was compared to late postnatal treatment (from day 4, equivalent to ~5months in humans). Animals were treated with the FGFR3 inhibitor infigratinib and the effect on skeleton was thoroughly examined. We show that premature fusion of the skull base synchondroses occurs immediately after birth and leads to defective cranial development and foramen magnum stenosis in the mouse model to achondroplasia. This phenotype appears significantly restored by early infigratinib administration when compared to late treatment, which provides weak to no rescue. In contrast, the long bone growth is similarly improved by both early and late protocols. We provide clear evidence that immediate postnatal therapy is critical for normalization of skeletal growth in both the cranial base and long bones and the prevention of sequelae associated with achondroplasia. We also describe the limitations of early postnatal therapy, providing a paradigm-shifting argument for the development of prenatal therapy for achondroplasia.

Internet-Based Abnormal Chromosomal Diagnosis During Pregnancy Using a Noninvasive Innovative Approach to Detecting Chromosomal Abnormalities in the Fetus: Scoping Review.

Chromosomal abnormalities are genetic disorders caused by chromosome errors, leading to developmental delays, birth defects, and miscarriages. Currently, invasive procedures such as amniocentesis or chorionic villus sampling are mostly used, which carry a risk of miscarriage. This has led to the need for a noninvasive and innovative approach to detect and prevent chromosomal abnormalities during pregnancy. This review aims to describe and appraise the potential of internet-based abnormal chromosomal preventive measures as a noninvasive approach to detecting and preventing chromosomal abnormalities during pregnancy. A thorough review of existing literature and research on chromosomal abnormalities and noninvasive approaches to prenatal diagnosis and therapy was conducted. Electronic databases such as PubMed, Google Scholar, ScienceDirect, CENTRAL, CINAHL, Embase, OVID MEDLINE, OVID PsycINFO, Scopus, ACM, and IEEE Xplore were searched for relevant studies and articles published in the last 5 years. The keywords used included chromosomal abnormalities, prenatal diagnosis, noninvasive, and internet-based, and diagnosis. The review of literature revealed that internet-based abnormal chromosomal diagnosis is a potential noninvasive approach to detecting and preventing chromosomal abnormalities during pregnancy. This innovative approach involves the use of advanced technology, including high-resolution ultrasound, cell-free DNA testing, and bioinformatics, to analyze fetal DNA from maternal blood samples. It allows early detection of chromosomal abnormalities, enabling timely interventions and treatment to prevent adverse outcomes. Furthermore, with the advancement of technology, internet-based abnormal chromosomal diagnosis has emerged as a safe alternative with benefits including its cost-effectiveness, increased accessibility and convenience, potential for earlier detection and intervention, and ethical considerations. Internet-based abnormal chromosomal diagnosis has the potential to revolutionize prenatal care by offering a safe and noninvasive alternative to invasive procedures. It has the potential to improve the detection of chromosomal abnormalities, leading to better pregnancy outcomes and reduced risk of miscarriage. Further research and development in this field is needed to make this approach more accessible and affordable for pregnant women.

Children had smaller brain volumes and cortical surface areas after prenatal opioid maintenance therapy exposure.

The studies have shown that infants with prenatal OMT exposure had smaller brain volumes than non-exposed controls, but long-term outcome data are lacking. We examined 5-13-year-old OMT-exposed children with brain MRI and tested motor and visual-motor functions and possible associations between brain morphology and outcome. To this retrospective cohort study, we recruited 55 children with prenatal OMT exposure and 59 age- and gender-matched controls. They were examined with brain MRI, Movement-ABC and Beery-VMI. MRI images were processed with the Free Surfer® software to obtain volumetrics and estimates of cortical surface area and thickness. We used a general linear regression model (GLM) to calculate group differences. The children in the OMT group had smaller mean total intracranial volume (ICV), 1407 cm3 (CI 95% 1379-1434) versus 1450 cm3 (CI 95% 1423-1476) in the control group (p = 0.026). After adjusting for ICV, significant group differences persisted for volumes of amygdala, basal ganglia and mid-posterior part of corpus callosum. Cortical surface area was smaller in the left caudal middle frontal gyrus and the right inferior parietal lobule in the OMT-group. Visual-motor function was significantly correlated with ICV. Prenatal OMT exposure may alter early brain development with possible negative long-term functional consequences.

Abstracts of the ISPD 28th International Conference on Prenatal Diagnosis and Therapy, 7-10 July 2024, Boston.

Abstracts of the ISPD 28th International Conference on Prenatal Diagnosis and Therapy, 7-10 July 2024, Boston.

Abstract Author Index of the ISPD 28th International Conference on Prenatal Diagnosis and Therapy, Boston, Massachusetts, United States, 7–10 July 2024

Abstract Author Index of the ISPD 28th International Conference on Prenatal Diagnosis and Therapy, Boston, Massachusetts, United States, 7–10 July 2024

Abstracts of the ISPD 28th International Conference on Prenatal Diagnosis and Therapy, 7-10 July 2024, Boston.

Abstracts of the ISPD 28th International Conference on Prenatal Diagnosis and Therapy, 7-10 July 2024, Boston.

Prenatal and Pregnancy Management of Congenital Adrenal Hyperplasia.

Management of patients with congenital adrenal hyperplasia (CAH) poses challenges during pregnancy and prenatal stages, impacting fertility differently in men and women. Women with CAH experience menstrual irregularities due to androgen and glucocorticoid precursor interference with endometrial development and ovulation. Genital surgeries for virilization and urogenital anomalies further impact fertility and sexual function, leading to reduced heterosexual relationships among affected women. Fertility rates vary, with a lower prevalence of motherhood, primarily among those with classic CAH, necessitating optimized hormonal therapy for conception. Monitoring optimal disease control during pregnancy poses challenges due to hormonal fluctuations. Men with CAH often experience hypogonadotrophic hypogonadism and complications like testicular adrenal rest tissue, impacting fertility. Regular monitoring and intensified glucocorticoid therapy may restore spermatogenesis. Genetic counselling is vital to comprehend transmission risks and prenatal implications. Prenatal dexamethasone treatment in affected female fetuses prevents virilization but raises ethical and safety concerns, necessitating careful consideration and further research. The international "PREDICT" study aims to establish safer and more effective prenatal therapy in CAH, evaluating dosage, safety, and long-term effects.

The Conundrum of Mechanics Versus Genetics in Congenital Hydrocephalus and Its Implications for Fetal Therapy Approaches: A Scoping Review.

Recent advances in gene therapy, particularly for single-gene disorders (SGDs), have led to significant progress in developing innovative precision medicine approaches that hold promise for treating conditions such as primary hydrocephalus (CH), which is characterized by increased cerebrospinal fluid (CSF) volumes and cerebral ventricular dilation as a result of impaired brain development, often due to genetic causes. CH is a significant contributor to childhood morbidity and mortality and a driver of healthcare costs. In many cases, prenatal ultrasound can readily identify ventriculomegaly as early as 14-20weeks of gestation, with severe cases showing poor neurodevelopmental outcomes. Postnatal surgical approaches, such as ventriculoperitoneal shunts, do not address the underlying genetic causes, have high complication rates, and result in a marginal improvement of neurocognitive deficits. Prenatal somatic cell gene therapy (PSCGT) promises a novel approach to conditions such as CH by targeting genetic mutations in utero, potentially improving long-term outcomes. To better understand the pathophysiology, genetic basis, and molecular pathomechanisms of CH, we conducted a scoping review of the literature that identified over 160 published genes linked to CH. Mutations in L1CAM, TRIM71, MPDZ, and CCDC88C play a critical role in neural stem cell development, subventricular zone architecture, and the maintenance of the neural stem cell niche, driving the development of CH. Early prenatal interventions targeting these genes could curb the development of the expected CH phenotype, improve neurodevelopmental outcomes, and possibly limit the need for surgical approaches. However, further research is needed to establish robust genotype-phenotype correlations and develop safe and effective PSCGT strategies for CH.

Placental Chorioangiomas: A Single Tertiary Center Experience

Abstract Background Chorioangiomas are benign vascular placental tumors. Although most of them remain small and are asymptomatic, large tumors (>4 cm) may cause maternal or fetal complications. Methods We report seven cases of chorioangioma over a span of 8 years in a single tertiary center managed either conservatively or with necessary intervention. All cases were followed up and postnatal outcomes were recorded. Results Six cases were diagnosed in the second trimester and one in the third trimester by ultrasound. Four were managed conservatively, while three of them required prenatal therapy: one interstitial laser and the other two an intrauterine arterial embolization of the feeder vessel. One underwent a rescue intrauterine fetal transfusion before definitive embolization. Conservatively managed patients developed gestational hypertension and growth restriction. They had low birth weight and needed neonatal intensive care. There was one intrauterine demise (IUD) and two healthy neonates in the cases that needed a fetal intervention. Conclusion The management of chorioangioma is dynamic and challenging, ranging from conservative to prenatal intervention. Treatment failure can result in serious complications adversely affecting pregnancy outcomes. However, regular monitoring by ultrasound and Doppler surveillance with timely interventions can lead to good neonatal and maternal outcomes.

The need for assisted ventilation corroborates the effectiveness of antenatal corticosteroid therapy in preventing premature lamb mortality

In premature births, deficiency and/or inactivation of surfactant and incomplete development of lung occur, leading to pulmonary complications and greater need for ventilatory interventions. Prenatal corticosteroid therapy is used to improve neonatal lung function and, thus, may reduce mortality and lower incidence and severity of lung injury. Therefore, this study aimed to assess the need for ventilatory support in preterm lambs subjected or not to prenatal betamethasone treatment, and to evaluate the effectiveness on neonatal survival. Lambing was induced and 13 premature lambs were assigned to Corticosteroid Group (n = 8; lambs from ewes subjected previously to 0.5 mg/kg betamethasone, IM, at 133 days of pregnancy) and Control Group (n = 5; non-treated lambs). Lambs were evaluated for vitality, neurologic reflexes, vital functions and birth weight. Three ventilatory modalities were preconized for critical lambs, according to specific criteria: mask oxygen therapy, self-inflating bag with tracheal tube and mechanical ventilation. Non-treated lambs had lower vitality score, muscle tonus and respiratory rate compared to Corticosteroid Group. Ventilatory support was needed for 3 Control lambs and only 1 Corticosteroid neonate. Corticosteroid lamb required significant less time-frame between birth and onset of ventilatory assistance and remained under ventilation for a shorter time. Percentage of ventilated non-treated lambs correlated negatively with birth weight, muscle tone, heart and respiratory rate. In conclusion, antenatal betamethasone treatment reduces the need for ventilatory assistance in premature lambs. Additionally, mortality is low when a protocol for inducing pulmonary maturity (maternal corticosteroid therapy) and/or ventilatory interventions are employed, ensuring the survival of premature lambs.

Experiences of Pregnant Women Undergoing Prenatal Gentle Yoga at Griya Kamini Gianyar

During pregnancy, most women experience psychological and emotional changes, and it is not uncommon for a mother to feel worried about potential problems. Concerns may include the possibility of losing her beauty or the baby being abnormal. Prenatal gentle yoga, a modification of prenatal yoga with a gentle birth approach, is offered at Griya Kamini Gianyar. This practice involves deep yoga therapy to support a healthy and fit pregnancy and labor. This study aimed to understand the experiences of pregnant mothers undergoing Prenatal Gentle Yoga at Griya Kamini Gianyar. The research design used in this study employs a qualitative interpretative method to understand the real experiences of pregnant women undergoing Prenatal Gentle Yoga Therapy at Griya Kamini Gianyar. The research results identified seven major themes: Positive Anticipation, Stress Management, Hope for Socializing, Connecting with Babies, Fitness and Flexibility, Professional Instructor Attitudes, and Managing Pain and Discomfort. The overarching theme identified is Stress Management, indicating that Prenatal Gentle Yoga is practiced by pregnant mothers to manage their emotions and ensure a smooth birth. Overall, yoga can be a valuable tool for pregnant mothers to manage pain and discomfort. With a careful and thoughtful approach, yoga can help pregnant mothers experience a more comfortable pregnancy, both physically and mentally.

Effect of prenatal glucocorticoid therapy on hearing screening in premature infants

Objective:To explore the effect of prenatal glucocorticoids therapy on hearing screening in premature infants Methods:Data of 693 preterm infants with gestational age of 24-34+6weeks admitted to theJiangxi Maternal and Child Health Hospital within 24 h after birth from June 2022 to June 2023 were retrospectively analyzed. The infants were divided into the DXM group （544 cases） and the non-DXM group （149 cases） based on whether dexamethasone （DXM） was administered prenatally. General data of preterm infants and parturients in two groups were compared, and the effects of different doses and timing of DXM on hearing screening were analyzed. Results:In the terms of preliminary hearing screening. the pass rate of initial hearing screening in DXM group was significantly higher than that in non-DXM group（53.9% vs 35.6%）, with statistical significance（P<0.05）. Further subgroup analysis showed that the passing rate of preliminary hearing screening in adequate prenatal dose（=4 doses） DXM group（58.1%） was significantly higher than that in insufficient group（48.0%） and excessive group（42.4%）, with statistical significance（P<0.05）. Administering DXM 48 hours to 7 days before birth resulted in a higher pass rate for initial hearing screening compared to administration <48 hours or >7 days before birth （56.4% vs. 48.6%）, with a statistically significant difference （P < 0.05）. In terms of re-hearing screening, the pass rate of secondary hearing screening was not significantly correlated with DXM treatment（P>0.05）, but was significantly correlated with gestational age, birth weight, hospital stays, invasive mechanical ventilation, and common neonatal diseases（bronchopulmonary dysplasia, respiratory distress syndrome）（P<0.05）. Among them, bronchopulmonary dysplasia was an independent risk factor forsecondary hearing screening referral（P<0.05）. Conclusion:A single course of adequate dexamethasone use within 48 h-7 d of prenatal has a positive effect on the preliminary hearing screening of preterm infants.

Prenatal AAV9-GFP administration in fetal lambs results in transduction of female germ cells and maternal exposure to virus

Prenatal somatic cell gene therapy (PSCGT) could potentially treat severe, early-onset genetic disorders such as spinal muscular atrophy (SMA) or muscular dystrophy. Given the FDA-approval of adeno-associated virus serotype 9 (AAV9) vectors in infants with SMA, we tested the safety and biodistribution of AAV9-GFP (clinical-grade and dose) in fetal lambs to understand safety and efficacy after umbilical vein (UV) or intracranial (IC) injection on embryonic day 75 (E75). UV-injection led to widespread biodistribution of vector genomes in all examined lamb tissues and in maternal uteruses at harvest (E96 or E140; term=E150). There was robust GFP expression in brain, spinal cord, dorsal root ganglia (DRGs), without DRG toxicity and excellent transduction of diaphragm and quadriceps muscles. However, we found evidence of systemic toxicity (fetal growth restriction) and maternal exposure to the viral vector (transient elevation of total bilirubin and a trend towards elevation in anti-AAV9 antibodies). There were no antibodies against GFP in ewes or lambs. Analysis of fetal gonads demonstrated GFP expression in female (but not male) germ cells, with low levels of integration-specific reads, without integration in select protooncogenes. These results suggest potential therapeutic benefit of AAV9 PSCGT for neuromuscular disorders but warrant caution for exposure of female germ cells.

Enhancing fetal outcomes in GCK-MODY pregnancies: a precision medicine approach via non-invasive prenatal GCK mutation detection.

Mutations in the GCK gene cause Maturity Onset Diabetes of the Young (GCK-MODY) by impairing glucose-sensing in pancreatic beta cells. During pregnancy, managing this type of diabetes varies based on fetal genotype. Fetuses carrying a GCK mutation can derive benefit from moderate maternal hyperglycemia, stimulating insulin secretion in fetal islets, whereas this may cause macrosomia in wild-type fetuses. Modulating maternal glycemia can thus be viewed as a form of personalized prenatal therapy, highly beneficial but not justifying the risk of invasive testing. We therefore developed a monogenic non-invasive prenatal diagnostic (NIPD-M) test to reliably detect the transmission of a known maternal GCK mutation to the fetus. A small amount of fetal circulating cell-free DNA is present in maternal plasma but cannot be distinguished from maternal cell-free DNA. Determining transmission of a maternal mutation to the fetus thus implies sequencing adjacent polymorphisms to determine the balance of maternal haplotypes, the transmitted haplotype being over-represented in maternal plasma. Here we present a series of such tests in which fetal genotype was successfully determined and show that it can be used to guide therapeutic decisions during pregnancy and improve the outcome for the offspring. We discuss several potential hurdles inherent to the technique, and strategies to overcome these. Our NIPD-M test allows reliable determination of the presence of a maternal GCK mutation in the fetus, thereby allowing personalized in utero therapy by modulating maternal glycemia, without incurring the risk of miscarriage inherent to invasive testing.

Identification of a novel intronic variant of ATP6V0A2 in a Han-Chinese family with cutis laxa.

Cutis laxa is a connective tissue disease caused by abnormal synthesis or secretion of skin elastic fibers, leading to skin flabby and saggy in various body parts. It can be divided into congenital cutis laxa and acquired cutis laxa, and inherited cutis laxa syndromes is more common in clinic. In this study, we reported a case of a Han-Chinese male newborn with ATP6V0A2 gene variant leading to cutis laxa. The proband was identified by whole-exome sequencing to determine the novel variant, and their parents were verified by Sanger sequencing. Bioinformatics analysis and minigene assay were used to verify the effect of this variant on splicing function. The main manifestations of the proband are skin laxity, abnormal facial features, and enlargement of the anterior fontanelle. Whole-exome sequencing showed that the newborn carried a non-canonical splicing-site variant c.117 + 5G > T, p. (?) in ATP6V0A2 gene. Sanger sequencing showed that both parents of the proband carried the heterozygous variant. The results of bioinformatics analysis and minigene assay displayed that the variant site affected the splicing function of pre-mRNA of the ATP6V0A2 gene. In this study, it was identified that ATP6V0A2 gene c. 117 + 5G > T may be the cause of the disease. The non-canonical splicing variants of ATP6V0A2 gene were rarely reported in the past, and this variant expanded the variants spectrum of the gene. The functional study of minigene assay plays a certain role in improving the level of evidence for the pathogenicity of splicing variants, which lays a foundation for prenatal counseling and follow-up gene therapy.

Folate-mediated Transport of Nanoparticles across the Placenta.

In this study, a prototype of a targeted nanocarrier for drug delivery for prenatal therapy of the developing fetus was developed and examined in vitro and ex vivo. The folate transport mechanism in the human placenta was utilized as a possible pathway for the transplacental delivery of targeted nanoparticles. Several types of folic acid-decorated polymeric nanoparticles were synthesized and characterized. During transport studies of targeted and non-targeted fluorescent nanoparticles across the placental barrier, the apparent permeability values, uptake, transfer indices, and distribution in placental tissue were determined. The nanoparticles had no effect on BeWo b30 cell viability. In vitro, studies showed significantly higher apparent permeability of the targeted nanoparticles across the cell monolayers as compared to the nontargeted nanoparticles (Pe = 5.92 ± 1.44 ×10-6 cm/s for PLGA-PEG-FA vs. 1.26 ± 0.31 ×10-6 cm/s for PLGA-PEG, P < 0.05), and the transport of the targeted nanoparticles was significantly inhibited by excess folate. Ex vivo placental perfusion showed significantly greater accumulation of the targeted nanoparticles in the placental tissue (4.31 ± 0.91%/g for PLGA-PEG-FA vs. 2.07 ± 0.26%/g for PLGA-PEG). The data obtained suggested different mechanisms for the uptake and transplacental transfer of targeted versus nontargeted nanoparticles. This targeted nanoformulation may be a promising strategy for fetal drug therapy.

Fetal circular shunt in Ebstein's anomaly and non-steroidal anti-inflammatory treatment.

A circular shunt is a poor prognostic factor associated with Ebstein's anomaly. Targeting the constriction of the ductus arteriosus (DA) in order to limit or resolve the circular shunt, has been shown to improve fetal outcomes. Prenatal non-steroidal anti-inflammatory drugs (NSAIDs) have been known to constrict the DA. Recently, prenatal NSAIDs have been used for that purpose in the treatment of circular shunt. Limited research shows that it may be an effective treatment leading to improved fetal outcomes. In this article, we did an extensive review of literature to describe this therapy's effectiveness and outcomes. 82% of fetuses were able to achieve ductal constriction with prenatal NSAID therapy. For fetuses who achieved ductal constriction, fetal demise was less likely (6%) when compared to those who were unable to achieve the same (50%). Of all the fetuses with hydrops, 50% had resoluation of hydrops with prenatal NSAID treatment.

Combination of Prenatal Gentle Yoga with Dhikr to Reduce The Anxiety Level of Pregnant Women

Anxiety in pregnant women should receive special attention. This psychological problem can even continue into the postpartum period, contributing to the emergence of baby blues and even postnatal depression. The level of anxiety in pregnant women can be minimized with non-pharmacological measures such as prenatal gentle yoga. This study aims to determine the effect of gentle yoga therapy and prenatal dhikr on the anxiety level of pregnant women in the Makassar Urban Area. This research used a pre-experimental design with a one group pretest and posttest design, with a sample of 25 pregnant women. This research uses prenatal gentle yoga and dhikr therapy interventions to reduce anxiety during pregnancy. Univariate analysis was carried out to obtain information regarding sample characteristics such as age, education, parity and gestational age. Bivariate analysis was carried out to find out what happened before and after prenatal gentle yoga and dhikr therapy. The results of the study showed that there was a difference in the level of anxiety of pregnant women (p= 0.000) before and after receiving gentle yoga and dhikr prenatal therapy intervention. In this study, gentle yoga prenatal therapy combined with dhikr was proven to be able to reduce anxiety levels in pregnant women, so that education and socialization can be given to pregnant women so that it becomes a habit.&#x0D;

산전⋅산후 물리치료에 대한 가임기 여성의 인식조사연구

산전⋅산후 물리치료에 대한 가임기 여성의 인식조사연구

Microinjection With Nanoparticles to Deliver Drugs in Prenatal Lung Explants - A Pilot Study for Prenatal Therapy in Congenital Diaphragmatic Hernia

BackgroundFetoscopic endoluminal tracheal occlusion (FETO) improves the survival rate in fetuses with severe congenital diaphragmatic hernia (CDH). We hypothesize that prenatal therapies into the trachea during FETO can further improve outcomes. Here, we present an ex vivo microinjection technique with rat lung explants to study prenatal therapy with nanoparticles. MethodsWe used microsurgery to isolate lungs from rats on embryonic day 18. We injected chitosan nanoparticles loaded with fluorescein (FITC) into the trachea of the lung explants. We compared the difference in biodistribution of two types of nanoparticles, functionalized IgG-conjugated nanoparticles (IgG-nanoparticles) and bare nanoparticles after 24 h culture with immunofluorescence (IF). We used IF to mark lung epithelial cells with E-cadherin and to investigate an apoptosis (Active-caspase 3) and inflammatory marker (Interleukin, IL-6) and compared its abundance between the two experimental groups and control lung explants. ResultsWe detected the presence of nanoparticles in the lung explants, and the relative number of nanoparticles to cells was 2.49 fold higher in IgG-nanoparticles than bare nanoparticles (p < 0.001). Active caspase-3 protein abundance was similar in the control, bare nanoparticles (1.20 fold higher), and IgG-nanoparticles (1.34 fold higher) groups (p = 0.34). Similarly, IL-6 protein abundance was not different in the control, bare nanoparticles (1.13 fold higher), and IgG-nanoparticles (1.12 fold higher) groups (p = 0.33). ConclusionsFunctionalized nanoparticles had a higher presence in lung cells and this did not result in more apoptosis or inflammation. Our proof-of-principle study will guide future research with therapies to improve lung development prenatally. Levels of EvidenceN/A Type of StudyAnimal and laboratory study.