Maternal "mirror" syndrome: Evaluating the benefits of fetal therapy.

OBJECTIVE: To evaluate maternal and perinatal outcomes following fetal intervention in the context of maternal "mirror" syndrome. STUDY DESIGN: A multicenter retrospective study of all cases of fetal hydrops complicated by maternal "mirror" syndrome and treated by any form of fetal therapy between 1995 and 2022. Medical records and ultrasound images of all cases were reviewed. "Mirror" syndrome was defined as fetal hydrops and/or placentomegaly associated with the maternal development of pronounced edema, with or without pre-eclampsia. Fetal hydrops was defined as the presence of abnormal fluid collections in ≥2 body cavities. RESULTS: Twenty-one pregnancies met the inclusion criteria. Causes of fetal hydrops and/or placentomegaly included fetal lung lesions (n = 9), twin-twin transfusion syndrome (n = 6), severe fetal anemia (n = 4), and others (n = 2). Mean gestational age at "mirror" presentation was 27.0 ± 3.8 weeks. Maternal "mirror" syndrome was identified following fetal therapeutic intervention in 14 cases (66.6%). "Mirror" symptoms resolved or significantly improved before delivery in 8 (38.1%) cases with a mean interval from fetal intervention to maternal recovery of 13.1 days (range 4-35). Three women needed to be delivered because of worsening "mirror" syndrome. Of the 21 pregnancies treated (27 fetuses), there were 15 (55.5%) livebirths, 7 (25.9%) neonatal deaths and 5 (18.5%) intra-uterine deaths. CONCLUSION: Following successful treatment and resolution of fetal hydrops, maternal "mirror" syndrome can improve or sometimes completely resolve before delivery. Furthermore, the recognition that "mirror" syndrome may arise only after fetal intervention necessitates hightened patient maternal surveillance in cases of fetal hydrops.

Transforming congenital heart disease management: Advances in fetal cardiac interventions.

This review addresses the transformative advancements in fetal cardiac interventions (FCI) for congenital heart diseases (CHD), with a particular focus on aortic stenosis with evolving hypoplastic left heart syndrome, pulmonary atresia with an intact ventricular septum, and HLHS with an intact atrial septum (HLHS-IAS). We outline the specific FCI techniques employed, the refined criteria for selecting appropriate fetal and maternal candidates, and the promising yet varied outcomes associated with these procedures. Procedural strategies and clinical decision-making are examined as we take into account the fetal pathophysiology and the benefits and risks of early intervention. We highlight the role of multidisciplinary teams in improving technical success and managing immediate procedural complications, which have led to significant improvements in procedural outcomes. Additionally, the review discusses the long-term outcomes, challenges, and future research directions in FCI, emphasizing the necessity for continuous innovation and collaboration across specialties to advance the management of CHD. The integration of new technologies and research findings holds the promise of further enhancing FCI success rates and patient outcomes.

National registry of thoracoamniotic shunting using a double-basket catheter: A post-marketing surveillance registry of 295 patients with fetal hydrothorax.

OBJECTIVE: We report on the 1-year outcomes of fetuses who underwent thoracoamniotic shunting (TAS) with a double-basket catheter for fetal hydrothorax (FHT) using a national post-marketing surveillance registry. METHODS: This surveillance study was conducted for cases enrolled between 2011 and 2019. Preoperative, operative, and postoperative findings and outcomes had to be reported through the national surveillance website. RESULTS: Forty-three institutes enrolled 295 patients. In 60 patients, associated abnormalities were diagnosed after birth. Among the 235 patients with isolated hydrothorax, the survival rate at 1 year of age was 70.5%. Among these patients, 89% did not require oxygen or other respiratory support. The 1-year survival rate in complicated cases was 27%. Trisomy 21 was the most common associated problem (40%). Catheter associated problems, including dislocation (25%), obstruction (24%), and preterm rupture of the membranes (6%) were observed, but there were no severe maternal complications. TAS before 29.5 weeks of gestation (odds ratio [OR] 0.16) and skin edema and ascites (OR 0.06) were risk factors for death at one year, whereas appropriate shunt location for >28 days (OR 4.2) was a protective factor. CONCLUSION: We report a favorable survival rate in fetuses with isolated FHT treated with this double-basket catheter.

Single-Center Incidence and Patterns of Stroke in Early Renal Anhydramnios After Serial Amnioinfusions.

The Renal Anhydramnios Fetal Therapy (RAFT) trial is a study of serial amnioinfusions to prevent lethal neonatal pulmonary hypoplasia from early renal anhydramnios. Infant neurologic outcomes were not originally evaluated. We describe the high incidence of stroke observed among infants in the treatment arm of the trial at our center.

Fetal aortic valvuloplasty as the first step in a complex therapeutic strategy.

BACKGROUND: Fetal aortic valvuloplasty (FAV) is proposed to prevent hypoplastic left heart syndrome due to fetal critical aortic stenosis. OBJECTIVE: to report our experience on FAV as the first step in a complex therapeutic strategy. METHOD: Series of patients with FAV over an 18-year period. RESULTS: 27 FAVs were performed in 26 fetuses, with technical success in 82% (22/27) and periprocedural fetal demise in 22% (6/27), decreasing to 15% in the second half-cohort. Loss to follow-up was due to birth or postnatal therapy in other centers (5) and termination of pregnancy (1), A normal-sized LV at birth was observed in 46% (6/13), 4 neonates underwent aortic valvuloplasty and 2 cardiac surgeries, with 5/6 achieving biventricular circulation at 28 days, and 3 transplant-free survival at mid-term follow-up. The 7/13 born with a borderline LV underwent LV rehabilitation strategy, with survival at 28 days in 4/7 and at mid-term in 3: one with biventricular circulation, one with a ventricle-and-a-half repair, and one lost to follow-up. CONCLUSION: FAV was feasible in most cases, with no maternal complications, and biventricular circulation at 28 days in ∼40% of survivors. After FAV, a diverse range of postnatal cardiac interventions are performed, reflecting the challenging innovation in current cardiovascular therapy.

The role of fetal therapy in the management of mirror syndrome: a narrative review.

OBJECTIVES: Mirror syndrome (MS) is a condition characterized by the presence of maternal, fetal, and placental edema and is reversible through delivery or pregnancy termination. As fetal hydrops itself may be amenable to treatment, we sought to determine outcomes for MS primarily managed by fetal therapy through a narrative review of the literature and cases managed at our fetal center. STUDY DESIGN: PubMed, Embase, Web of Science, Scopus, and Google Scholar databases were searched through January 2024 using key words: mirror syndrome, Ballantyne's syndrome, fetal hydrops, maternal hydrops, pseudotoxemia, triple edema, maternal recovery, fetal therapy, and resolution. Manuscripts describing primary management by fetal therapy that included maternal and fetal outcomes were identified. Clinical details of MS patients managed with fetal therapy at our center were also included for descriptive analysis. RESULTS: 16 of 517 manuscripts (3.1%) described fetal therapy as the primary intended treatment in 17 patients. 3 patients managed at our center were included in the analysis. Among 20 patients undergoing primary fetal therapy for management of mirror syndrome, median gestational age of presentation was 24 weeks and 5 days gestation; predominant clinical findings were maternal edema (15/20), proteinuria (10/20), pulmonary edema (8/20), and hypertension (8/20); the primary laboratory abnormalities were anemia (8/20) and elevated creatinine or transaminases (5/20). Condition-specific fetal therapies led to resolution of hydrops in 17 (85%) cases and MS in 19 (95%) cases. The median time to hydrops resolution was 7.5 days and to resolution of mirror syndrome was 10 days. Fetal therapy prolonged pregnancy by a median of 10 weeks with a median gestational age of 35 weeks and 5 days at delivery. All women delivered for indications other than mirror syndrome and 19/20 fetuses survived. CONCLUSION: In appropriately selected cases, MS often resolves after fetal therapy of hydrops allowing for safe pregnancy prolongation with good maternal and infant outcomes.

Prenatal diagnosis and in utero treatment of congenital adrenal hyperplasia: An up-to-date comprehensive review.

Congenital adrenal hyperplasia (CAH) is a term that encompasses a wide range of conditions that affect the adrenals. Diagnosis and treatment before birth are important as irreparable birth defects can be avoided, decreasing the need for surgical intervention later in life, especially regarding genitalia anomalies. Although early implementation of dexamethasone in the prenatal treatment of CAH has been controversial, there is recent evidence that this treatment can reduce long-term complications.

Antenatal Administration of Extracellular Vesicles Derived From Amniotic Fluid Stem Cells Improves Lung Function in Neonatal Rats With Congenital Diaphragmatic Hernia.

BACKGROUND: The severity of pulmonary hypoplasia is a main determinant of outcome for babies with congenital diaphragmatic hernia (CDH). Antenatal administration of extracellular vesicles derived from amniotic fluid stem cells (AFSC-EVs) has been shown to rescue morphological features of lung development in the rat nitrofen model of CDH. Herein, we evaluated whether AFSC-EV administration to fetal rats with CDH is associated with neonatal improvement in lung function. METHODS: AFSC-EVs were isolated by ultracentrifugation and characterized by size, morphology, and canonical marker expression. At embryonic (E) day 9.5, dams were gavaged with olive oil (control) or nitrofen to induce CDH. At E18.5, fetuses received an intra-amniotic injection of either saline or AFSC-EVs. At E21.5, rats were delivered and subjected to a tracheostomy for mechanical ventilation (flexiVent system). Groups were compared for lung compliance, resistance, Newtonian resistance, tissue damping and elastance. Lungs were evaluated for branching morphogenesis and collagen quantification. RESULTS: Compared to healthy control, saline-treated pups with CDH had fewer airspaces, more collagen deposition, and functionally exhibited reduced compliance and increased airway resistance, elastance, and tissue damping. Conversely, AFSC-EV administration resulted in improvement of lung mechanics (compliance, resistance, tissue damping, elastance) as well as lung branching morphogenesis and collagen deposition. CONCLUSIONS: Our studies show that the rat nitrofen model reproduces lung function impairment similar to that of human babies with CDH. Antenatal administration of AFSC-EVs improves lung morphology and function in neonatal rats with CDH. LEVEL OF EVIDENCE: N/A (animal and laboratory study).

Intra-Amniotic Sildenafil and Rosiglitazone Late in Gestation Ameliorate the Pulmonary Hypertension Phenotype in Congenital Diaphragmatic Hernia.

BACKGROUND: Pulmonary hypertension remains difficult to manage in congenital diaphragmatic hernia (CDH). Prenatal therapy may ameliorate postnatal pulmonary hypertension. We hypothesized that intra-amniotic (IA) injection of either sildenafil, a phosphodiesterase 5 inhibitor, or rosiglitazone, a PPAR-γ agonist, or both late in gestation would decrease the detrimental pulmonary vascular remodeling seen in CDH and improve peripheral pulmonary blood flow. METHODS: Pregnant rats were gavaged with nitrogen on embryonic day (E) 9.5 to induce fetal CDH. Sildenafil and/or rosiglitazone were administered to each fetus via an intra-amniotic injection after laparotomy on the pregnant dam at E19.5, and fetuses delivered at E21.5. Efficacy measures were gross necropsy, histology, peripheral blood flow assessment using intra-cardiac injection of a vascular tracer after delivery, and protein expression analysis. RESULTS: Intra-amniotic injections did not affect fetal survival, the incidence of CDH, or lung weight-to-body weight ratio in CDH fetuses. IA sildenafil injection decreased pulmonary vascular muscularization, and rosiglitazone produced an increase in peripheral pulmonary blood flow distribution. The combination of sildenafil and rosiglitazone decreased pulmonary artery smooth muscle cell proliferation. These intra-amniotic treatments did not show any negative effects in either CDH fetuses or control fetuses. CONCLUSION: IA injection of sildenafil and rosiglitazone late in gestation ameliorates the pulmonary hypertensive phenotype of CDH and may have utility in clinical translation. LEVEL OF EVIDENCE: Not applicable.

Double Myelomeningocele Repair by Fetal Surgery with a Single Micro-Hysterotomy.

INTRODUCTION: Open spina bifida (OSB) is the most common congenital anomaly of the central nervous system. It is associated with severe neurodevelopmental delay, motor impairment, hydrocephalus, and bowel and bladder dysfunction. In selected cases, intrauterine spina bifida repair has been shown to improve neonatal outcomes. Rarely, the spine can have a double defect compromising two different segments and there is a lack of evidence on the feasibility and benefits of intrauterine repair in these cases. CASE PRESENTATION: We present a case with both cervicothoracic and lumbosacral myelomeningocele, Arnold-Chiari malformation type II and bilateral ventriculomegaly, that was treated successfully at 25 weeks with open micro-neurosurgery. Double myelomeningocele was successfully treated through a single 2-cm micro-hysterotomy, by performing external versions to sequentially expose and repair both defects. Weekly postoperative follow-up showed no progression of ventriculomegaly or complications attributable to the procedure. Preterm rupture of membranes prompted a conventional cesarean delivery at 32 weeks of gestation. Neurodevelopmental outcome at 20 months was within normal ranges, having achieved ambulation without orthopedic support and with no need for ventriculoperitoneal shunting. CONCLUSION: This report demonstrates for the first time the feasibility of double OSB repair through a single 2-cm micro-hysterotomy, suggesting that selected isolated cases of double myelomeningocele could be candidates for fetal intervention. Further prospective studies should be carried out to assess the potential benefit of double OSB intrauterine open repair.

Prenatal Diagnosis of Fetal Aqueductal Stenosis: A Multicenter Prospective Observational Study through the North American Fetal Therapy Network.

INTRODUCTION: A critical component of an evidence-based reassessment of in-utero intervention for fetal aqueductal stenosis (fetal AS) is determining if the prenatal diagnosis can be accurately made at a gestational age amenable to in-utero intervention. METHODS: A multicenter, prospective, observational study was conducted through the North American Fetal Therapy Network (NAFTNet). Pregnancies complicated by severe central nervous system (CNS) ventriculomegaly (lateral ventricle diameter >15 mm) not secondary to a primary diagnosis (myelomeningocele, encephalocele, etc.) were recruited at diagnosis. Imaging and laboratory findings were recorded in an online REDCap database. After evaluation, investigators were asked to render their degree of confidence in the diagnosis of fetal AS. The prenatal diagnosis was compared to the postnatal diagnosis obtained through neonatal neuroimaging. Performance characteristics of ultrasound and magnetic resonance imaging (MRI) were calculated, as was the mean gestational age at diagnosis. RESULTS: Between April 2015 and October 2022, eleven NAFTNet centers contributed 64 subjects with severe fetal CNS ventriculomegaly. Of these, 56 had both prenatal and postnatal diagnoses recorded. Ultrasound revealed 32 fetal AS true positives, 4 false positives, 7 false negatives, and 13 true negatives, rendering a sensitivity of 0.82, a specificity of 0.76, a positive predictive value of 0.89, and a negative predictive value of 0.65. The mean gestational age at diagnosis by ultrasound was 25.5 weeks (std +/- 4.7 weeks). The proportion of agreement (true positive + true negative/n) was highest at 24 weeks gestation. For fetal MRI (n = 35), the sensitivity for fetal AS was 0.95, specificity was 0.69, positive predictive value was 0.84, and negative predictive value was 0.90. MRI was performed at 25 weeks on average. CONCLUSION: The prenatal diagnosis of fetal AS can be made with accuracy at a gestational age potentially amenable to in-utero intervention. Only 7% of subjects were incorrectly diagnosed prenatally with fetal AS by ultrasound and 11% by MRI. Diagnostic accuracy of fetal AS will likely improve with increased experience.

Neonatal Survival After Serial Amnioinfusions for Bilateral Renal Agenesis: The Renal Anhydramnios Fetal Therapy Trial.

Importance: Early anhydramnios during pregnancy, resulting from fetal bilateral renal agenesis, causes lethal pulmonary hypoplasia in neonates. Restoring amniotic fluid via serial amnioinfusions may promote lung development, enabling survival. Objective: To assess neonatal outcomes of serial amnioinfusions initiated before 26 weeks' gestation to mitigate lethal pulmonary hypoplasia. Design, Setting, and Participants: Prospective, nonrandomized clinical trial conducted at 9 US fetal therapy centers between December 2018 and July 2022. Outcomes are reported for 21 maternal-fetal pairs with confirmed anhydramnios due to isolated fetal bilateral renal agenesis without other identified congenital anomalies. Exposure: Enrolled participants initiated ultrasound-guided percutaneous amnioinfusions of isotonic fluid before 26 weeks' gestation, with frequency of infusions individualized to maintain normal amniotic fluid levels for gestational age. Main Outcomes and Measures: The primary end point was postnatal infant survival to 14 days of life or longer with dialysis access placement. Results: The trial was stopped early based on an interim analysis of 18 maternal-fetal pairs given concern about neonatal morbidity and mortality beyond the primary end point despite demonstration of the efficacy of the intervention. There were 17 live births (94%), with a median gestational age at delivery of 32 weeks, 4 days (IQR, 32-34 weeks). All participants delivered prior to 37 weeks' gestation. The primary outcome was achieved in 14 (82%) of 17 live-born infants (95% CI, 44%-99%). Factors associated with survival to the primary outcome included a higher number of amnioinfusions (P = .01), gestational age greater than 32 weeks (P = .005), and higher birth weight (P = .03). Only 6 (35%) of the 17 neonates born alive survived to hospital discharge while receiving peritoneal dialysis at a median age of 24 weeks of life (range, 12-32 weeks). Conclusions and Relevance: Serial amnioinfusions mitigated lethal pulmonary hypoplasia but were associated with preterm delivery. The lower rate of survival to discharge highlights the additional mortality burden independent of lung function. Additional long-term data are needed to fully characterize the outcomes in surviving neonates and assess the morbidity and mortality burden. Trial Registration: ClinicalTrials.gov Identifier: NCT03101891.

Development and in-vitro characterization of a novel fetal vesicoamniotic shunt - The Vortex shunt.

OBJECTIVES: To develop and test a novel vesicoamniotic shunt (VAS) to treat fetal lower urinary tract obstruction (LUTO), decrease dislodgement and optimize shunt deployment in-vitro. METHODS: Vesicoamniotic shunt design objectives included: (1) robust and atraumatic fixation elements, (2) kink resistant conduit to adjust to fetal movement and growth, (3) one-way pressure valve to facilitate bladder cycling, and (4) echogenic deployment visualization aids. The force to dislodge the novel Vortex shunt was compared with existing commercially available shunts in a bench-top porcine bladder model. Sonographic echogenicity was evaluated with ultrasound-guided deployment, and the shunt valve pressure measured. RESULTS: A prototype novel Vortex shunt was developed using braided nitinol "umbrella-type" ends with a kink-resistant stem incorporating an internal one-way valve. The peak force required to dislodge the Vortex shunt was significantly higher than commercially available shunts (p < 0.01). Shunt deployment in the bench-top model was easily confirmed with ultrasound guidance and the brisk decompression of the inflated porcine bladder thereafter. In-vitro valve gauge pressure testing mirrored bladder pressures in human LUTO cases. CONCLUSION: In-vitro testing shows that the Vortex shunt may improve deployment, sonographic visualization, kink resistance, and dynamic size adjustment. Validation in preclinical animal models are warranted and currently underway.

Outcomes of laser surgery for stage I twin-twin transfusion syndrome.

OBJECTIVE: A recent randomized controlled trial (RCT) demonstrated no difference in 6 month survival in expectantly managed stage I twin-twin transfusion syndrome (TTTS) patients and those undergoing immediate laser surgery. We aimed to describe outcomes following immediate laser surgery at a single fetal surgery center. METHODS: A retrospective study of monochorionic diamniotic twins diagnosed with stage I TTTS who underwent laser surgery between 16 and 26 gestational weeks from 2006 to 2019. The primary outcome was 6 month survivorship. Intact survival was also assessed. Secondarily, outcomes were compared to the RCT expectant management group. RESULTS: Of 126 consecutive stage I TTTS patients, 114 (90.5%) met inclusion criteria. Median (range) gestational age at delivery was 34.1 (20.6-39.4) weeks. At 6 months, the proportion of patients with at-least-one survivor in the single-center-laser cohort was 97.4%, with 88.6% dual survivorship. Neurological morbidity outcomes were available in 110 pregnancies (220 fetuses). Severe neurological morbidity occurred in 2.7% (6/220), and 6 month survival without severe neurological morbidity was 90.0%. Outcomes compared favorably with the RCT expectant management group. CONCLUSIONS: Given favorable survival and neurological outcomes, laser surgery is a reasonable treatment option for stage I TTTS at experienced fetal surgery centers. Further study is warranted to optimize treatment strategies.

Open surgery for in utero repair of spina bifida: Microneurosurgery versus standard technique - A systematic review.

BACKGROUND/OBJECTIVES: Prenatal myelomeningocele (MMC) repair has been shown to improve neurological outcomes. It has been suggested that decreases in the hysterotomy diameter during surgery can improve perinatal outcomes without altering neurologic outcomes. The objective of this study is to describe and compare the main maternal and fetal outcomes of fetuses undergoing open surgery for MMC repair, through the different modifications (standard-classical, mini-hysterotomy, and microneurosurgery). DATA SOURCE: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Ovid, SciELO, LILACS, PROSPERO. RESULTS: From a total of 112 studies, seven case series were selected including 399 fetuses with open fetal surgery, five studies using the classical technique (n = 181), one with mini-hysterotomy (n = 176), and one with the microneurosurgery technique (n = 42). The mini-hysterotomy and microneurosurgery techniques presented a lower risk of preterm delivery (21.4% and 30%, respectively) compared to the classic technique (47.3%), premature rupture of membranes (78%, 62%, and 72.5 %, respectively), oligohydramnios (0% and 72.5%, respectively), dehiscence of hysterotomy, maintaining the same frequency of Chiari reversion (78%, 62%, and 72.5%, respectively), postnatal correction requirement (0%, 4.8%, and 5.8%, respectively), and lower frequency of requirement for a ventriculoperitoneal shunt placement (13.0%, 7.5%, and 29.1%, respectively). CONCLUSION: The least invasive techniques (minihysterotomy-microneurosurgery) are possible and reproduceable, as they are associated with better maternal and perinatal outcomes.

Fetal open spinal dysraphism repair through a mini-hysterotomy: Influence of gestational age at surgery on children's ability to walk.

OBJECTIVE: To analyze the impact of gestational age (GA) at the time of fetal open spinal dysraphism (OSD) repair through a mini-hysterotomy on the ability of children to walk. METHODS: Children who underwent in utero repair of OSD and had formal neurological assessment after 2.5 years of age were compared regarding their ability to walk in relation to pre-surgical predictors. RESULTS: Sixty-nine children fulfilled the inclusion criteria. Among them, 63.7% (44/69) were able to walk with or without orthesis. Fetal OSD correction performed earlier in gestation (from 19.7 to 26.9 weeks) was associated with a higher probability of walking with or without orthesis (p = 0.033). The median GA at delivery was 35.3 weeks. Multivariate binary logistic regression showed that the upper anatomical level of the OSD ( L5) (p < 0.004; OR: 10.31 [95% CI: 2.07-51.28]) and GA at the time of fetal surgery (p = 0.026; OR = 0.68 [95% CI: 0.48-0.95]) were independent predictors of the postnatal ability to walk with or without orthesis. CONCLUSION: Fetuses with OSD who were operated on earlier in pregnancy (range: 19.7-26.9 weeks), were more likely to walk with or without orthesis.

Serial neurosonography in fetuses with congenital heart defects shows mild delays in cortical development.

INTRODUCTION: Neurodevelopmental delay is more common in children born with congenital heart defects (CHD), even with optimal perinatal and peri-operative care. It is hypothesized that fetuses with CHD are prone to neurological impairment in utero due to their cardiac defect, possibly leading to delayed cortical development. METHODS: Cerebral cortical maturation was assessed with advanced neurosonographic examinations every 4 weeks in fetuses with CHD and compared to control fetuses. Five different primary fissures and four areas were scored (ranging 0-5) by blinded examiners using a cortical maturation scheme. RESULTS: Cortical staging was assessed in 574 ultrasound examinations in 85 CHD fetuses and 61 controls. Small differences in grading were seen in Sylvian and cingulate fissures. (Sylvian fissure: -0.12 grade, 95% CI (-0.23; -0.01) p = 0.05, cingulate fissure: -0.24 grade, 95% CI (-0.38; -0.10) p = <0.001. Other cortical areas showed normal maturation as compared to control fetuses. CONCLUSION: Small differences were seen in three of the nine analyzed cortical areas in CHD fetuses, in contrast to previous reports on progressive third-trimester delay. The clinical implications of the small differences however, remain unknown.

Induction of Tertiary Phase Epileptiform Discharges after Postasphyxial Infusion of a Toll-Like Receptor 7 Agonist in Preterm Fetal Sheep.

BACKGROUND: Toll-like receptor (TLR) agonists are key immunomodulatory factors that can markedly ameliorate or exacerbate hypoxic-ischemic brain injury. We recently demonstrated that central infusion of the TLR7 agonist Gardiquimod (GDQ) following asphyxia was highly neuroprotective after 3 days but not 7 days of recovery. We hypothesize that this apparent transient neuroprotection is associated with modulation of seizure-genic processes and hemodynamic control. METHODS: Fetuses received sham asphyxia or asphyxia induced by umbilical cord occlusion (20.9 ± 0.5 min) and were monitored continuously for 7 days. GDQ 3.34 mg or vehicle were infused intracerebroventricularly from 1 to 4 h after asphyxia. RESULTS: GDQ infusion was associated with sustained moderate hypertension that resolved after 72 h recovery. Electrophysiologically, GDQ infusion was associated with reduced number and burden of postasphyxial seizures in the first 18 h of recovery (p < 0.05). Subsequently, GDQ was associated with induction of slow rhythmic epileptiform discharges (EDs) from 72 to 96 h of recovery (p < 0.05 vs asphyxia + vehicle). The total burden of EDs was associated with reduced numbers of neurons in the caudate nucleus (r2 = 0.61, p < 0.05) and CA1/2 hippocampal region (r2 = 0.66, p < 0.05). CONCLUSION: These data demonstrate that TLR7 activation by GDQ modulated blood pressure and suppressed seizures in the early phase of postasphyxial recovery, with subsequent prolonged induction of epileptiform activity. Speculatively, this may reflect delayed loss of early protection or contribute to differential neuronal survival in subcortical regions.