Detrimental effect of prenatal progesterone exposure on anxiety and depressive-like responses in adult male and female rat offspring: Role of plasma, hippocampal corticosterone and hippocampal progesterone receptors.

In clinical practice, the use of exogenous progesterone (Pro) is often required in assisted reproduction programs due to reduced levels of the hormone and the risk of miscarriage. Exposure to the hormone reduces anxiety in rodents, but the long-term effects of prenatal exposure in adult offspring are unknown. Therefore, the present study was designed to investigate the effect of prenatal Pro treatment on anxiety- and depression-like behavior and the effect on plasma, hippocampal corticosterone (CORT) and hippocampal progesterone receptor (PR) in young adult male and female rat offspring. The behavioral responses of offspring of both sexes were tested in the open field, and the elevated plus maze tests, and for depressive-like behavior in the sucrose preference test, the forced swimming test and the splash test. CORT levels and PR expression were measured by ELISA. The results indicate that prenatal Pro exposure at low and high doses (10 and 50 mg kg-1, s.c. during G0-G10) induces anxiogenic and depressive-like effects compared to vehicle-treated controls, which are associated with high plasma and hippocampal CORT levels and upregulated hippocampal PR in male and female adult offspring. Our results demonstrate that prenatal Pro exposure has detrimental effects on the emotional status of male and female adult offspring, which may be associated with long-term changes in hormonal homeostasis.

Maternal treatment with a selective delta-opioid receptor agonist during gestation has a sex-specific pro-cognitive action in offspring: mechanisms involved.

Background: There is growing evidence that the treatment of several mental disorders can potentially benefit from activation of delta-opioid receptors. In the future, delta-agonists with a safe pharmacological profile can be used for the treatment of mood disorders in pregnant women. However, the data on prenatal exposure to delta-opioid agonists are missing. The present study is aimed to test the hypothesis that the activation of delta-opioid receptors during gravidity has positive effects on the behaviour accompanied by changes in glutamate and monoamine neurotransmission. Methods: Gestating Wistar rats were chronically treated with a selective delta-agonist SNC80 or vehicle. Adult male and female offspring underwent novel object recognition (for the assessment of cognition) and open field (for the assessment of anxiety and habituation) tests, followed by in vivo electrophysiological examination of the activity of hippocampal glutamate and midbrain serotonin (5-HT) and dopamine neurons. Results: We found that the maternal treatment with SNC80 did not affect the offspring's anxiety, habituation, and 5-HT neuronal firing activity. Female offspring of SNC80-treated dams exhibited improved novelty recognition associated with decreased firing rate and burst activity of glutamate and dopamine neurons. Conclusion: Maternal treatment with delta-opioid agonists during gestation may have a pro-cognitive effect on offspring without any negative effects on anxiety and habituation. The putative pro-cognitive effect might be mediated via mechanism(s) involving the firing activity of hippocampal glutamate and mesolimbic dopamine neurons.

Open Fetal Surgery for Ventricular-Amniotic Valve Implantation in Aqueductal Stenosis-Dependent Severe Fetal Hydrocephalus: A Case Report with 7-Year Follow-Up.

INTRODUCTION: Fetal ventriculomegaly is one of the most commonly diagnosed central nervous system pathologies of the second trimester, occurring with a frequency of 0.3-0.5/1,000 births. Severe fetal ventriculomegaly (SVM) may necessitate intrauterine intervention. Most such interventions have been made percutaneously with ultrasound guidance insertion of a pigtail catheter, which sadly often became obstructed or migrated. CASE PRESENTATION: Our case report presents the possibility of ventriculo-amniotic valve implantation (VAVI) by classic hysterotomy in isolated severe fetal hydrocephalus (IVSM) due to aqueductal stenosis. The patient was operated on similarly to open fetal surgery MOMS criteria at 24+4/7 GA, with an initial lateral ventricular dimension of 22.5 mm. A female newborn was delivered by elective cesarean section at 31+1/7 GA due to PPROM (Apgar 10' 8 points, birth weight 1,600 g), required CPAP, and removal of the drainage system due to infection and narrow lateral ventricles. Evans index (EI) gradual increase and clinical symptoms of high-pressure hydrocephalus after 10 days required a ventricle-peritoneal shunt (VPS) implantation. The newborn was discharged home after 28 days with stabile hydrocephalus (EI: 0.59-0.6), in good clinical condition. The 7-year follow-up was complicated by epilepsy, VPS shunt infections, delay in motor and intellectual functions (mild to moderate), and symptoms of atypical autism, the phenotype possibly related to a variant in ZEB2 gene. CONCLUSION: Intrauterine VAVI is a one-step procedure that is effective in draining CFS. The limitations of the method remain complications due to preterm labor and infection of the drainage system.

The Effects of Prenatal Pravastatin Treatment in the Rabbit Fetal Growth Restriction Model.

Fetal growth restriction (FGR) remains without an effective prenatal treatment. Evidence from murine FGR models suggests a beneficial effect of prenatal pravastatin. Since the rabbit hemodichorial placenta more closely resembles the human condition, we investigated the effects of prenatal maternal pravastatin administration in the rabbit FGR model. At a gestational age of 25 days (term 31d), pregnant dams underwent partial uteroplacental vessel ligation (UPVL) in one uterine horn to induce FGR, leaving the other horn as a control. Dams were randomized to either receive 5 mg/kg/d pravastatin dissolved in their drinking water or normal drinking water until delivery. At GA 30d, the rabbits were delivered and were divided into four groups: control without pravastatin (C/NoPrav), FGR without pravastatin (FGR/NoPrav), FGR with pravastatin (FGR/Prav), and controls with pravastatin (C/Prav). The newborn rabbits underwent pulmonary functional assessment and neurobehavioral assessment, and they were harvested for alveolar morphometry or neuropathology. The placentas underwent histology examination and RNA expression. Birth weight was lower in the FGR groups (FGR/Prav, FGR/NoPrav), but there was no difference between FGR/Prav and C/NoPrav. No differences were noted in placental zone proportions, but eNOS in FGR/Prav placentas and VEGFR-2 in FGR/Prav and C/Prav were upregulated. There were no differences in pulmonary function assessment and alveolar morphometry. FGR/Prav kittens had increased neurosensory scores, but there were no differences in neuromotor tests, neuron density, apoptosis, and astrogliosis. In conclusion, in the rabbit FGR model, pravastatin upregulated the expression of VEGFR-2 and eNOS in FGR placentas and was associated with higher neurosensory scores, without measurable effects on birthweight, pulmonary function and morphology, and neuron density.

Treatment, not delivery, of the late preterm and term fetus with supraventricular arrhythmia.

OBJECTIVE: While in-utero treatment of sustained fetal supraventricular arrhythmia (SVA) is standard practice in the previable and preterm fetus, data are limited on best practice for late preterm (34 + 0 to 36 + 6 weeks), early term (37 + 0 to 38 + 6 weeks) and term (> 39 weeks) fetuses with SVA. We reviewed the delivery and postnatal outcomes of fetuses at ≥ 35 weeks of gestation undergoing treatment rather than immediate delivery. METHODS: This was a retrospective case series of fetuses presenting at ≥ 35 weeks of gestation with sustained SVA and treated transplacentally at six institutions between 2012 and 2022. Data were collected on gestational age at presentation and delivery, SVA diagnosis (short ventriculoatrial (VA) tachycardia, long VA tachycardia or atrial flutter), type of antiarrhythmic medication used, interval between treatment and conversion to sinus rhythm and postnatal SVA recurrence. RESULTS: Overall, 37 fetuses presented at a median gestational age of 35.7 (range, 35.0-39.7) weeks with short VA tachycardia (n = 20), long VA tachycardia (n = 7) or atrial flutter (n = 10). Four (11%) fetuses were hydropic. In-utero treatment led to restoration of sinus rhythm in 35 (95%) fetuses at a median of 2 (range, 1-17) days; this included three of the four fetuses with hydrops. Antiarrhythmic medications included flecainide (n = 11), digoxin (n = 7), sotalol (n = 11) and dual therapy (n = 8). Neonates were liveborn at 36-41 weeks via spontaneous vaginal delivery (23/37 (62%)) or Cesarean delivery (14/37 (38%)). Cesarean delivery was indicated for fetal SVA in two fetuses, atrial ectopy or sinus bradycardia in three fetuses and obstetric reasons in nine fetuses that were in sinus rhythm at the time of delivery. Twenty-one (57%) cases were treated for recurrent SVA after birth. CONCLUSION: In-utero treatment of the near term and term (≥ 35-week) SVA fetus is highly successful even in the presence of hydrops, with the majority of cases delivered vaginally closer to term, thereby avoiding unnecessary Cesarean section. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Prenatal vitamin D supplementation mitigates inflammation-related alveolar remodeling in neonatal mice.

The development of chronic lung disease in the neonate, also known as bronchopulmonary dysplasia (BPD), is the most common long-term complication in prematurely born infants. In BPD, the disease-characteristic inflammatory response culminates in nonreversible remodeling of the developing gas exchange area, provoked by the impact of postnatal treatments such as mechanical ventilation (MV) and oxygen treatment. To evaluate the potential of prenatal treatment regimens to modulate this inflammatory response and thereby impact the vulnerability of the lung toward postnatal injury, we designed a multilayered preclinical mouse model. After administration of either prenatal vitamin D-enriched (VitD+; 1,500 IU/g food) or -deprived (VitD-; <10 IU/kg) food during gestation in C57B6 mice (the onset of mating until birth), neonatal mice were exposed to hyperoxia (FiO2 = 0.4) with or without MV for 8 h at days 5-7 of life, whereas controls spontaneously breathed room air. Prenatal vitamin D supplementation resulted in a decreased number of monocytes/macrophages in the neonatal lung undergoing postnatal injury together with reduced TGF-ß pathway activation. In consequence, neonatal mice that received a VitD+ diet during gestation demonstrated less extracellular matrix (ECM) remodeling upon lung injury, reflected by the reduction of pulmonary α-smooth muscle actin-positive fibroblasts, decreased collagen and elastin deposition, and lower amounts of interstitial tissue in the lung periphery. In conclusion, our findings support strategies that attempt to prevent vitamin D insufficiency during pregnancy as they could impact lung health in the offspring by mitigating inflammatory changes in neonatal lung injury and ameliorating subsequent remodeling of the developing gas exchange area.NEW & NOTEWORTHY Vitamin D-enriched diet during gestation resulted in reduced lung inflammation and matrix remodeling in neonatal mice exposed to clinically relevant, postnatal injury. The results underscore the need to monitor the subclinical effects of vitamin D insufficiency that impact health in the offspring when other risk factors come into play.

Visible light-curable methacrylated glycol chitosan hydrogel patches for prenatal closure of fetal myelomeningocele.

In this study, we prepared visible light-curable methacrylated glycol chitosan (MGC) hydrogel patches for the prenatal treatment of fetal myelomeningocele (MMC) and investigated their feasibility using a retinoic acid-induced fetal MMC rat model. 4, 5, and 6 w/v% of MGC were selected as candidate precursor solutions, and photo-cured for 20 s, because the resulting hydrogels were found to possess concentration dependent tunable mechanical properties and structural morphologies. Moreover, these materials exhibited no foreign body reactions with good adhesive properties in animal studies. The inflammation scoring assessment in vivo exhibited the absence of foreign body reactions in MGC hydrogel treated lesion. The complete epithelial coverage of MMC was made with using 6 w/v% MGC hydrogel followed by well-organized granulation along with noticeable decrease of abortion rate and wound size that highlight the therapeutic potential for the prenatal treatment of fetal MMC.

An update on the long-term outcomes of prenatal dexamethasone treatment in congenital adrenal hyperplasia.

First-trimester prenatal treatment with glucocorticoid (GC) dexamethasone (DEX) in pregnancies at risk for classic congenital adrenal hyperplasia (CAH) is associated with ethical dilemmas. Though effective in reducing virilisation in girls with CAH, it entails exposure to high doses of GC in fetuses that do not benefit from the treatment. The current paper provides an update on the literature on outcomes of prenatal DEX treatment in CAH cases and unaffected subjects. Long-term follow-up research is still needed to determine treatment safety. In addition, advances in early prenatal diagnostics for CAH and sex-typing as well as studies assessing dosing effects of DEX may avoid unnecessary treatment and improve treatment safety.

Maternal Administration of the CNS-Selective Sobetirome Prodrug Sob-AM2 Exerts Thyromimetic Effects in Murine MCT8-Deficient Fetuses.

Background: Monocarboxylate transporter 8 (MCT8) deficiency is a rare X-linked disease where patients exhibit peripheral hyperthyroidism and cerebral hypothyroidism, which results in severe neurological impairments. These brain defects arise from a lack of thyroid hormones (TH) during critical stages of human brain development. Treatment options for MCT8-deficient patients are limited and none have been able to prevent or ameliorate effectively the neurological impairments. This study explored the effects of the TH agonist sobetirome and its CNS-selective amide prodrug, Sob-AM2, in the treatment of pregnant dams carrying fetuses lacking Mct8 and deiodinase type 2 (Mct8/Dio2 KO), as a murine model for MCT8 deficiency. Methods: Pregnant dams carrying Mct8/Dio2 KO fetuses were treated with 1 mg of sobetirome/kg body weight/day, or 0.3 mg of Sob-AM2/kg body weight/day for 7 days, starting at embryonic day 12.5 (E12.5). As controls, pregnant dams carrying wild-type and pregnant dams carrying Mct8/Dio2 KO fetuses were treated with daily subcutaneous injections of vehicle. Dams TH levels were measured by enzyme-linked immunosorbent assay (ELISA). Samples were extracted at E18.5 and the effect of treatments on the expression of triiodothyronine (T3)-dependent genes was measured in the placenta, fetal liver, and fetal cerebral cortex by real-time polymerase chain reaction. Results: Maternal sobetirome treatment led to spontaneous abortions. Sob-AM2 treatment, however, was able to cross the placental as well as the brain barriers and exert thyromimetic effects in Mct8/Dio2 KO fetal tissues. Sob-AM2 treatment did not affect the expression of the T3-target genes analyzed in the placenta, but it mediated thyromimetic effects in the fetal liver by increasing the expression of Dio1 and Dio3 genes. Interestingly, Sob-AM2 treatment increased the expression of several T3-dependent genes in the brain such as Hr, Shh, Dio3, Kcnj10, Klf9, and Faah in Mct8/Dio2 KO fetuses. Conclusions: Maternal administration of Sob-AM2 can cross the placental barrier and access the fetal tissues, including the brain, in the absence of MCT8, to exert thyromimetic actions by modulating the expression of T3-dependent genes. Therefore, Sob-AM2 has the potential to address the cerebral hypothyroidism characteristic of MCT8 deficiency from fetal stages and to prevent neurodevelopmental alterations in the MCT8-deficient fetal brain.

New data on efficacy of valacyclovir in secondary prevention of maternal-fetal transmission of cytomegalovirus.

OBJECTIVE: Congenital cytomegalovirus (CMV) infection is the leading cause of non-genetic hearing and neurological deficits. The aim of our study was to evaluate the efficacy and safety of valacyclovir (VCV) treatment in preventing CMV transmission to the fetus after maternal primary infection. METHODS: This was a retrospective, multicenter study evaluating the rate of maternal-fetal CMV transmission in pregnancies with maternal primary CMV infection treated with VCV at a dosage of 8 g per day (VCV group) compared with a control group of untreated women. Each case underwent virological testing to confirm maternal primary infection and to provide accurate dating of onset of infection. The primary outcome was the presence of congenital CMV infection at birth diagnosed based on polymerase chain reaction analysis of saliva, urine and/or blood samples. The efficacy of VCV treatment was assessed using logistic regression analysis adjusted for a propensity score. RESULTS: In total, 143 patients were included in the final analysis, of whom 59 were in the VCV group and 84 were in the untreated control group. On propensity-score-adjusted analysis, VCV treatment was significantly associated with an overall reduction in the rate of maternal-fetal CMV transmission (odds ratio, 0.40 (95% CI, 0.18-0.90); P = 0.029). The rate of maternal-fetal CMV transmission, determined at birth, in the VCV vs control group was 7% (1/14) vs 10% (1/10) after periconceptional maternal primary infection (P = 1.00), 22% (8/36) vs 41% (19/46) after first-trimester maternal primary infection (P = 0.068) and 25% (2/8) vs 52% (14/27) after second-trimester maternal primary infection (P = 0.244). When analyzing the efficacy of VCV treatment according to maternal viremia at treatment initiation, there was a trend towards greater efficacy when patients were viremia-positive (21% vs 43%; P = 0.072) compared with when they were viremia-negative (22% vs 17%; P = 0.659). Maternal side effects associated with VCV were mild and non-specific in most cases. CONCLUSION: Our findings indicate that VCV treatment of pregnant women with primary CMV infection reduces the risk of maternal-fetal transmission of CMV and may be effective in cases with primary infection in the first and second trimesters. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Diagnóstico e adesão do tratamento da sífilis gestacional em uma ubs do município de Caçador ­ Sc / Diagnosis and aderence to the treatment of gestational syphilis in a ubs in the municipality of Caçador ­ Sc / Diagnóstico y adherencia al tratamiento de la sífilis gestacional em una ubs del municipio de Caçador-Sc

A sífilis é uma doença infectocontagiosa, tendo a via sexual como a principal via de transmissão, mas podendo ser por via sanguínea e transplacentária. Apresenta-se, também, como gestacional e congênita, além das suas formas clínicas­ primária, secundária, terciária, latente recente e latente tardia ­ que auxiliam no tratamento. Objetivo: analisar a relação entre o diagnóstico e adesão do tratamento adequado na sífilis gestacional. Metodologia: Tratou-se de uma pesquisa descritiva, exploratória e retrospectiva com uma abordagem quantitativa. As variáveis foram obtidas através das fichas do Sistema de Informação de Agravos de Notificação (SINAN) da sífilis gestacional e congênita e dos prontuários da Unidade Básica de Saúde (UBS) Central no município de Caçador-SC no do período de 2018 a 2022. Os dados foram dispostos em tabelas e a análise realizada por meio da frequência relativa e absoluta. Resultados: Foram analisadas 61 mulheres com sífilis gestacional e 4 recém-nascidos com sífilis congênita. Destas,58 realizaram o tratamento, sendo os casos mais frequentes em mães de 21 a 25 anos. Observou-se que 93,10% das crianças notificadas tiverem o teste não treponêmico não reagente. Conclusão: houve baixa incidência de sífilis congênita, porém, elevado número de parceiros não tratados, o que reforça a importância da assistência no pré-natal para prevenção e seguimento do tratamento correto.

Syphilis is an infectious and contagious disease, having the sexual route as the main route of transmission, but it can also be via blood and transplacental. It is also presented as gestational and congenital, in addition to its clinical forms ­ primary, secondary, tertiary, recent latent and late latent ­ which help in the treatment. Objective: to analyze the relationship between diagnosis and adherence to adequate treatment in gestational syphilis. Methodology: It was a descriptive, exploratory, and retrospective research with a quantitative approach. The variables were recorded through the records of the Notifiable Diseases Information System (SINAN) of gestational and congenital syphilis and the medical records of the Central Basic Health Unit (UBS) in the municipality of Caçador-SC in the period from 2018 to 2022. The data were prescribed in tables and the analysis performed through relative and absolute frequency. Results: 61 women with gestational syphilis and 4 newborns with congenital syphilis were pregnant. Of these, 58 underwent treatment, with the most frequent cases in mothers aged 21 to 25 years. Note that 93.10% of the notified children had non-reactive non-treponemal test. Conclusion: there was a low incidence of congenital syphilis, however, a high number of untreated partners, which reinforces the importance of prenatal care for prevention and following the correct treatment.

La sífilis es una enfermedad infectocontagiosa, teniendo la vía sexual como principal vía de transmisión, pero también puede ser vía sanguínea y transplacentaria. También se presenta como gestacional y congénita, además de sus formas clínicas - primaria, secundaria, terciaria, latente reciente y latente tardía- que ayudan en el tratamiento. Objetivo: analizar la relación entre el diagnóstico y la adherencia al tratamiento adecuado en la sífilis gestacional. Metodología: Fue una investigación descriptiva, exploratoria y retrospectiva con enfoque cuantitativo. Las variables fueron obtenidas a través de los registros del Sistema de Información de Enfermedades de Declaración Obligatoria (SINAN) de sífilis gestacional y congénita y de las historias clínicas de la Unidad Básica Central de Salud (UBS) del municipio de Caçador-SC en el período de 2018 a 2022. datos se organizaron en tablas y el análisis se realizó mediante frecuencia relativa y absoluta. Resultados: Se analizaron 61 mujeres con sífilis gestacional y 4 recién nacidos con sífilis congénita. De estos, 58 recibieron tratamiento, siendo los casos más frecuentes en madres de 21 a 25 años. Se observó que el 93,10% de los niños notificados tenían prueba no treponémica no reactiva. Conclusión: hubo baja incidencia de sífilis congénita, sin embargo, alto número de parejas no tratadas, lo que refuerza la importancia del control prenatal para la prevención y seguimiento del correcto tratamiento.

Intra-amniotic transplantation of brain-derived neurotrophic factor-modified mesenchymal stem cells treatment for rat fetuses with spina bifida aperta.

BACKGROUND: Spina bifida aperta (SBA) is a relatively common clinical type of neural tube defect. Although prenatal fetal surgery has been proven to be an effective treatment for SBA, the recovery of neurological function remains unsatisfactory due to neuron deficiencies. Our previous results demonstrated that intra-amniotic transplanted bone marrow mesenchymal stem cells (BMSCs) could preserve neural function through lesion-specific engraftment and regeneration. To further optimize the role of BMSCs and improve the environment of defective spinal cords so as to make it more conducive to nerve repair, the intra-amniotic transplanted BMSCs were modified with brain-derived neurotrophic factor (BDNF-BMSCs), and the therapeutic potential of BDNF-BMSCs was verified in this study. METHODS: BMSCs were modified by adenovirus encoding a green fluorescent protein and brain-derived neurotrophic factor (Ad-GFP-BDNF) in vitro and then transplanted into the amniotic cavity of rat fetuses with spina bifida aperta which were induced by all-trans-retinoic acid on embryonic day 15. Immunofluorescence, western blot and real-time quantitative PCR were used to detect the expression of different neuron markers and apoptosis-related genes in the defective spinal cords. Lesion areas of the rat fetuses with spina bifida aperta were measured on embryonic day 20. The microenvironment changes after intra-amniotic BDNF-BMSCs transplantation were investigated by a protein array with 90 cytokines. RESULTS: We found that BDNF-BMSCs sustained the characteristic of directional migration, engrafted at the SBA lesion area, increased the expression of BDNF in the defective spinal cords, alleviated the apoptosis of spinal cord cells, differentiated into neurons and skin-like cells, reduced the area of skin lesions, and improved the amniotic fluid microenvironment. Moreover, the BDNF-modified BMSCs showed a better effect than pure BMSCs on the inhibition of apoptosis and promotion of neural differentiation. CONCLUSION: These findings collectively indicate that intra-amniotic transplanted BDNF-BMSCs have an advantage of promoting the recovery of defective neural tissue of SBA fetuses.

Prenatal interventions for fetal growth restriction in animal models: A systematic review.

Fetal growth restriction (FGR) in human pregnancy is associated with perinatal mortality, short- and long-term morbidities. No prenatal therapy is currently established despite decades of research. We aimed to review interventions in animal models for prenatal FGR treatment, and to seek the next steps for an effective clinical therapy. We registered our protocol and searched MEDLINE, Embase, and The Cochrane Library with no language restrictions, in accordance with the PRISMA guideline. We included all studies that reported the effects of any prenatal intervention in animal models of induced FGR. From 3257 screened studies, 202 describing 237 interventions were included for the final synthesis. Mice and rats were the most used animals (79%) followed by sheep (16%). Antioxidants (23%), followed by vasodilators (18%), nutrients (14%), and immunomodulators (12%) were the most tested therapy. Two-thirds of studies only reported delivery or immediate neonatal outcomes. Adverse effects were rarely reported (11%). Most studies (73%), independent of the intervention, showed a benefit in fetal survival or birthweight. The risk of bias was high, mostly due to the lack of randomization, allocation concealment, and blinding. Future research should aim to describe both short- and long-term outcomes across various organ systems in well-characterized models. Further efforts must be made to reduce selection, performance, and detection bias.

First Trimester Dexamethasone Treatment Is Not Associated With Alteration in Resting-state Connectivity at Adolescent or Adult Age.

CONTEXT: Prenatal treatment with dexamethasone (DEX) has been used to prevent virilization in females at risk of congenital adrenal hyperplasia (CAH). Both affected and unaffected girls, as well boys, are treated until the genotype and sex of the fetus is known (gestational weeks 10-12). After that, only affected girls are treated until term. Exposure to a high synthetic glucocorticoid dosage may alter the developmental trajectory of the brain, with alterations in resting-state functional connectivity of the brain at adult age. OBJECTIVE: To investigate resting-state functional connectivity in subjects at risk of having CAH, exposed to DEX treatment during the first trimester of fetal life, both in the whole brain and in 3 regions of interest (amygdala, hippocampus, and superior frontal gyrus). DESIGN, SETTING, AND PARTICIPANTS: Eighteen participants (8 females) at risk of having CAH, exposed to DEX treatment, and 38 controls (24 females), age range 16 to 26 years, from a single research institute, underwent functional magnetic resonance imaging of the brain during rest. We used 2 different approaches: an exploratory whole-brain analysis and seed-based analysis. For seed-based analysis, we chose 3 different brain regions (amygdala, hippocampus, and superior frontal gyrus) based on our previous findings and literature evidence. RESULTS: We did not observe any differences in functional connectivity during rest, either in the whole brain nor in seed-based connectivity analyses at this adolescent and young adult age. CONCLUSIONS: Our results are reassuring; however, future studies on larger samples and with more sensitive methodologies are needed to confirm these findings.

Ambulatory Blood Pressure Monitoring in Children and Adults Prenatally Exposed to Dexamethasone Treatment.

CONTEXT: The clinical use of dexamethasone (DEX) prenatally to reduce virilization of external genitalia in female fetuses with congenital adrenal hyperplasia (CAH) is efficient but still controversial. It remains challenging to prevent the excessive exposure of DEX in unborn healthy babies during the first trimester of pregnancy. OBJECTIVE: Since endogenous glucocorticoids contribute to the maintenance of blood pressure (BP) and since events during fetal life may program the fetus and affect future metabolic health, the aim of this study was to analyze ambulatory BP measurements in CAH-unaffected children and adults that were prenatally exposed to DEX treatment. METHODS: Ambulatory BP measurements were analyzed in 33 (16 female) DEX-treated participants aged 5.1 to 26.3 years (19 participants aged ≤ 18 years) and in 54 (28 female) age- and sex-matched apparently healthy controls aged 5.5 to 25.3 years (27 participants aged ≤ 18 years) with ambulatory normotension. RESULTS: Participants' age, height, weight, and body mass index were similar between the DEX-treated group and the control group. Heart rate, 24-hour BP, pulse pressure, and nighttime dipping did not statistically significantly differ between DEX-treated participants and controls. CONCLUSION: Our study suggests that prenatal DEX treatment in CAH-unaffected children and adults does not appear to adversely affect ambulatory BP later in life. Our observations need to be confirmed in larger studies.

Ebstein's anomaly: epidemiological analysis and presentation of different prenatal management.

OBJECTIVES: To present the crucial role of echocardiographic examination in perinatal care and analyze influence of prenatal treatment for neonatal outcome. Furthermore, the attempt to answer the question if there was any relationship between the occurrence of fetal Ebstein's anomaly and environmental risk factors in polish population. METHODS: Forty-five prenatal diagnoses of Ebstein's anomaly were compiled over the 21-year period (1998‒2018) form our single unit. The analysis included the assessment of maternal parameters (age, past obstetric history, and place of residence) and fetal parameters (sex, gestational age, anatomy, the fetal cardiovascular condition assessed by the CVPS, associated extracardiac anomalies or malformations, prenatal treatment, delivery and follow-up). RESULTS: The average age of gravida was 29.5 years (± 5.2 years) and gravidae <35 years of age accounted for 80% . There were 43 singleton pregnancies and 2 cases of multiple pregnancy. Ebstein's anomaly was mostly (averagely) diagnosed at 28th week of gestation. Forty-three fetuses had normal karyotypes and two had trisomy 21. Cardiomegaly was present in 91% (41) of fetuses. The average heart area to chest area ratio was 0.56 (± 0.12). In 21 cases, there was only fetal monitoring - echocardiographic examinations and postnatal mortality was 44.4%. In 5 cases, transplacental digoxin treatment was administered and mortality was: 40%. In another 5 cases, only steroid therapy was applied and postnatal mortality was 100%. Steroids and transplacental digoxin treatment were administered in 11 cases and mortality was 63.6%. In 3 last cases transplacental digoxin treatment, steroids and maternal hyperoxygenation therapy were given and mortality was 0%. Cesarean section rate was 49%. Moreover, due to Ebstein's anomaly regional peak of occurrence benzopyrene was deliberated as environmental risk factor. CONCLUSIONS: Fetal Ebstein's anomaly occurred in our population in healthy young women, expecting their first child and malformation was not related to fetus gender, nor to maternal health condition. Our data can be a new signal for the development of novel treatment strategies in therapy in fetuses with Ebstein's anomaly.

The Effect of Prenatal and Postnatal Treatment with Intravenous Immunoglobulin on Severity of Neonatal Hemochromatosis: The Tale of Two Brothers (Case Report).

Background Neonatal hemochromatosis (NH) is a rare condition that was the main reason for liver transplantation in infants. With the realization that NH results from the fetal complement-mediated liver injury, intravenous immunoglobulins (IVIG) were successfully introduced for the treatment. Case Presentation We present two cases of NH from the same family to illustrate the role of antenatal treatment with IVIG in alleviation and possible prevention of this serious morbidity. Conclusion A prenatal treatment and early postnatal administration of IVIG are effective ways to manage NH that help to reduce the severity of the symptoms, prevent liver failure, and avoid the need for liver transplantation.

Effects of Transplacental Dexamethasone Therapy on Fetal Immune-Mediated Complete Heart Block.

INTRODUCTION: Antibody-mediated complete atrioventricular block (CAVB) is considered irreversible. We sought to examine the effects of transplacental steroids on fetal AV conduction. METHODS: Fifty-nine fetuses diagnosed with CAVB at our center from 1996 to 2018 were reviewed. Routine dexamethasone administration to birth was used to limit cardiac inflammatory damage. Restoration of fetal AV conduction was classified as "unexpected" treatment response. RESULTS: CAVB resolved in 5/29 (17%) fetuses first treated ≤24-week gestation with 8 mg/day of dexamethasone, when compared with 0/30 (0%) when treatment was initiated later and/or at a starting dose of 4 mg/day (odds ratio 13.69; 95% confidence interval 0.72-260.13; p = 0.024). Treatment response was also associated with a faster ventricular rate at diagnosis (median [range]: 80 [60-97] beats per minute [bpm] vs. 58 [38-92] bpm; p = 0.0036). CAVB reappeared in all 5 responders either prenatally (n = 1) or postnatally before (n = 3) or after (n = 1) the first year of life. When compared with infants with treatment-resistant CAVB (median follow-up 10.3 years), responders (median follow-up 12.3 years) required postnatal pacing less frequent (2/5 [40%] vs. 45/49 [92%]; p = 0.013). CONCLUSIONS: In a subgroup of CAVB fetuses, dexamethasone transiently restored AV conduction. This was associated with a lower rate of postnatal pacing when compared with nonresponders.

Fetoscopic techniques for prenatal covering of gastroschisis in an ovine model are technically demanding and do not lead to permanent anchoring on the fetus until the end of gestation.

INTRODUCTION: This is the cumulative technical report on the operative procedures and limitations of fetoscopic bag insertion, intestinal bag placement, and bag fixation to the fetus in a series of pilot studies in an ovine model for prenatal treatment of gastroschisis. MATERIAL AND METHODS: In 24 German blackhead sheep, a surgically created gastroschisis was managed by fetoscopic placement of the extruded intestines into a bag. The bag was then fastened onto the fetal abdominal wall. Different materials (sterile gloves, latex condoms, laparosopic retrieval bags) and different fixation techniques (laparoscopic staplers, interrupted and continuous sutures) have been examined. The fetuses were retrieved and evaluated at the end of gestation. RESULTS: Uterine bag insertion was successful in 15 of 24 (62.5%) and intestinal bag placement in 10 of 15 available fetuses (66.6%). The main factor limiting fetoscopic procedures was chorioamniotic separation (CAS). Sterilized condoms provided the most appropriate type of bags and the V-Loc™ running suture, the most expedient type of fixation, which was achieved in 9 of the 10 fetuses (complete = 2, partially = 7) by using a three port access (5 mm and 2 × 3 mm). All bags were encountered completely or partially dislocated from the fetus at the end of gestation. CONCLUSIONS: Fetoscopic intestinal bag placement and fixation in gastroschisis technically demanding. None of the evaluated techniques led to permanent anchorage of the bag to the fetus. The development of specially designed instruments, bags and fixation methods is required to optimize this approach.

Prenatal Treatment of Thyroid Hormone Cell Membrane Transport Defect Caused by MCT8 Gene Mutation.

Background: Mutations of the thyroid hormone (TH)-specific cell membrane transporter, monocarboxylate transporter 8 (MCT8), produce an X-chromosome-linked syndrome of TH deficiency in the brain and excess in peripheral tissues. The clinical consequences include brain hypothyroidism causing severe psychoneuromotor abnormalities (no speech, truncal hypotonia, and spastic quadriplegia) and hypermetabolism (poor weight gain, tachycardia, and increased metabolism, associated with high serum levels of the active TH, T3). Treatment in infancy and childhood with TH analogues that reduce serum triiodothyronine (T3) corrects hypermetabolism, but has no effect on the psychoneuromotor deficits. Studies of brain from a 30-week-old MCT8-deficient embryo indicated that brain abnormalities were already present during fetal life. Methods: A carrier woman with an affected male child (MCT8 A252fs268*), pregnant with a second affected male embryo, elected to carry the pregnancy to term. We treated the fetus with weekly 500 µg intra-amniotic instillation of levothyroxine (LT4) from 18 weeks of gestation until birth at 35 weeks. Thyroxine (T4), T3, and thyrotropin (TSH) were measured in the amniotic fluid and maternal serum. Treatment after birth was continued with LT4 and propylthiouracil. Follow-up included brain magnetic resonance imaging (MRI) and neurodevelopmental evaluation, both compared with the untreated brother. Results: During intrauterine life, T4 and T3 in the amniotic fluid were maintained above threefold to twofold the baseline and TSH was suppressed by 80%, while maternal serum levels remained unchanged. At birth, the infant serum T4 was 14.5 µg/dL and TSH <0.01 mU/L compared with the average in untreated MCT8-deficient infants of 5.1 µg/ and >8 mU/L, respectively. MRI at six months of age showed near-normal brain myelination compared with much reduced in the untreated brother. Neurodevelopmental assessment showed developmental quotients in receptive language and problem-solving, and gross motor and fine motor function ranged from 12 to 25 at 31 months in the treated boy and from 1 to 7 at 58 months in the untreated brother. Conclusions: This is the first demonstration that prenatal treatment improved the neuromotor and neurocognitive function in MCT8 deficiency. Earlier treatment with TH analogues that concentrate in the fetus when given to the mother may further rescue the phenotype.