Jezid Miranda

Inflammation is a physiological and tightly regulated component of normal pregnancy, contributing to implantation, placental development, and the initiation of parturition. The placenta functions as an active immunological hub, coordinating innate and adaptive immune responses to maintain tolerance while protecting against infection. Preeclampsia and fetal growth restriction (FGR) are major causes of maternal and perinatal morbidity worldwide and represent central manifestations of placental disease. Increasing evidence indicates that these conditions share key pathophysiological mechanisms, including placental dysfunction and maladaptive maternal immune responses. When immune regulation at the maternal–fetal interface becomes disrupted, inflammatory pathways contribute to impaired placental development and vascular maladaptation. In this context, excessive immune activation—driven by inflammasome signaling, Th1/Th17 polarization, and altered natural killer and macrophage function—can compromise placental perfusion, promote antiangiogenic imbalance, and lead to systemic endothelial dysfunction. This review, therefore, focuses on how immune dysregulation contributes to placental dysfunction in preeclampsia and FGR, synthesizing current knowledge of the maternal–fetal immune interface and exploring therapeutic strategies that link pathogenic mechanisms to targeted interventions. A deeper understanding of placental immunology and inflammatory signaling is essential to develop precision therapies. Established therapies, including low-dose aspirin, low-molecular-weight heparin, and antenatal corticosteroids, aim to mitigate inflammation and optimize fetal outcomes, while adjunctive strategies target oxidative stress, nutritional deficits, and the maternal microbiome. Emerging approaches such as cytokine-targeted biologics, inflammasome inhibitors, and mesenchymal stem cell therapies show promise but require rigorous safety and efficacy evaluation. Future research should prioritize biomarker validation, pathway-specific interventions, and equitable implementation to reduce inflammation-driven pregnancy complications.

Objective: Angiogenic factors are elevated in fetal growth restriction (FGR), but their clinical value for assessing the severity of FGR and the potential influence of coexisting pre‐eclampsia has scarcely been investigated. In this study, our aim was to investigate the profile of maternal angiogenic factors across severity stages of fetal smallness compared with controls, analyzed overall and stratified by the presence or absence of pre‐eclampsia, and to investigate whether values of these angiogenic factors, such as placental growth factor (PlGF), soluble fms‐like tyrosine kinase‐1 (sFlt‐1) and the sFlt‐1/PlGF ratio, are helpful in determining the severity stage of fetal smallness. Methods: This was a prospective cohort study of women with a singleton pregnancy diagnosed with fetal smallness (defined as birth weight < 10 ^th centile) ( n = 604) between October 2010 and December 2017, compared with a control group of pregnant women with an appropriate‐for‐gestational‐age (AGA) singleton fetus (defined as birth weight ≥ 10 ^th centile) ( n = 424). At diagnosis, ultrasound was performed to assess estimated fetal weight (EFW) and Doppler pulsatility indices (PI) of the uterine artery (UtA), umbilical artery (UA), fetal middle cerebral artery (MCA) and ductus venosus (DV), and these parameters were monitored regularly until delivery. Cerebroplacental ratio (CPR) was calculated as MCA‐PI/UA‐PI. Small fetuses were classified as: small‐for‐gestational age (SGA) if EFW ≥ 3 ^rd and < 10 ^th centile, with normal Doppler parameters; FGR Stage I if either EFW < 3 ^rd centile, persistent MCA‐PI < 5 ^th centile, UA‐PI > 95 ^th centile, CPR < 5 ^th centile or UtA‐PI > 95 ^th centile; FGR Stage II if there was absent end‐diastolic flow in the UA; FGR Stage III if there was reversed end‐diastolic flow in the UA or DV‐PI ≥ 95 ^th centile; or FGR Stage IV if there was non‐reassuring cardiotocography or absent/reversed DV atrial flow. Maternal peripheral venous blood concentrations of PlGF and sFlt‐1 were determined using enzyme‐linked immunosorbent assay, and the sFlt‐1/PlGF ratio was calculated. Linear trend of proportions was tested using the Mantel–Haenszel chi‐square test. Results: Among AGA controls ( n = 424), SGA ( n = 192), FGR Stage I ( n = 380), FGR Stage II ( n = 16) and FGR Stages III–IV ( n = 16) fetuses, the proportion of cases with a sFlt‐1/PlGF ratio > 95 ^th centile was 12.7%, 7.8%, 30.8%, 43.8% and 62.5%, respectively ( P = 0.0001), and the median multiples of the median (MoM) values for the sFlt‐1/PlGF ratio were 0.55 (interquartile range (IQR), 0.19–2.00), 1.00 (IQR, 0.31–2.67), 3.03 (IQR, 0.91–8.20), 3.94 (IQR, 0.85–9.13) and 7.32 (IQR, 1.44–16.29), respectively ( P = 0.24). Pre‐eclampsia was diagnosed at any time between inclusion and delivery in 1.9% of controls, 3.6% of SGA, 21.1% of FGR Stage I, 37.5% of FGR Stage II and 50.0% of FGR Stages III–IV fetuses. Among all small fetuses with vs without pre‐eclampsia, the proportion of pregnancies with sFlt‐1/PlGF ratio > 95 ^th centile was 56.9% vs 15.4% ( P < 0.001) and the median MoM of the sFlt‐1/PlGF ratio was 8.11 (IQR, 3.83–27.09) vs 1.59 (IQR, 0.52–5.04) ( P = 0.18). Conclusions: Serum levels of angiogenic factors became more abnormal as the severity stage of fetal smallness increased. This association with severity was stronger in the presence of pre‐eclampsia. However, absolute values of serum levels showed substantial overlap in both the presence and the absence of pre‐eclampsia, making their use in determining the severity stage of fetal smallness challenging. © 2026 International Society of Ultrasound in Obstetrics and Gynecology.

Inflammation is a normal and essential feature of pregnancy, supporting implantation, placental development, and parturition. When dysregulated, however, inflammatory pathways contribute to major obstetric complications such as preeclampsia, fetal growth restriction (FGR), and preterm birth, which account for substantial maternal and perinatal morbidity and mortality. This review synthesizes current understanding of the maternal–fetal immune interface, examines how inflammation contributes to pregnancy disorders, and explores therapeutic strategies that link pathogenic mechanisms to targeted interventions. The placenta functions as an active immunological hub, coordinating innate and adaptive immune responses to maintain tolerance while protecting against infection. In preeclampsia and FGR, excessive activation—driven by inflammasome signaling, Th1/Th17 polarization, and altered natural killer and macrophage function—impairs placental perfusion, promotes antiangiogenic pathways, and induces systemic endothelial dysfunction. Established therapies, including low-dose aspirin, low-molecular-weight heparin, and antenatal corticosteroids, aim to mitigate inflammation and optimize fetal outcomes, while adjunctive strategies target oxidative stress, nutritional deficits, and the maternal microbiome. Emerging approaches such as cytokine-targeted biologics, inflammasome inhibitors, and mesenchymal stem cell therapies show promise but require rigorous evaluation of safety and efficacy. A deeper understanding of placental immunology and inflammatory signaling is essential to develop precision therapies. Future research should prioritize biomarker validation, pathway-specific interventions, and equitable implementation to reduce inflammation-driven pregnancy complications.

Objective: To report the prenatal diagnosis of CSPP1‐related Joubert Syndrome 21 (JS21) in a fetus with multiple congenital anomalies, highlighting the complementary role of detailed neuroimaging and molecular genetic testing. Methods: A fetus with suspected central nervous system anomalies underwent detailed prenatal ultrasound and fetal neurosonography, followed by magnetic resonance imaging (MRI) and exome sequencing. We reviewed prenatal imaging, molecular findings, and postnatal outcomes. Results: A 25‐year‐old G4P2011 patient with a history of adverse pregnancy outcomes associated with fetal malformations was referred at 32 weeks of gestation. Ultrasound findings included occipital meningocele, cerebellar vermis agenesis, and bilateral cleft lip and palate. Fetal MRI confirmed the characteristic molar tooth sign, raising suspicion of Joubert syndrome. Exome sequencing identified a homozygous canonical splice‐site variant in CSPP1, NM_001382391.1:c.2968 + 1G > A (rs587777142), classified as pathogenic according to ACMG/AMP criteria. The pregnancy resulted in the birth of a female neonate weighing 3165 g, and postnatal clinical and imaging evaluation supported the prenatal diagnosis of CSPP1- related JS21. Conclusions: This case illustrates the value of integrating detailed fetal neuroimaging with molecular genetic testing for the prenatal diagnosis of Joubert syndrome. Recognition of characteristic imaging findings can guide targeted interpretation of genetic results, allowing earlier diagnosis, more accurate counseling, and coordinated prenatal and postnatal care.

Syphilis during pregnancy remains a persistent global public health challenge. Untreated or inadequately treated syphilis infection during pregnancy contributes significantly to preventable perinatal morbidity and mortality. In the last five years, a resurgence of syphilis among pregnant women in several regions has led to a concerning rise in congenital syphilis cases. Vertical transmission can occur at any point during pregnancy or delivery, with the highest risk observed during primary and secondary stages of infection compared to latent phases. To align with the World Health Organization (WHO) target of reducing the vertical transmission rate below 0.05%, the International Federation of Gynecology and Obstetrics (FIGO) has developed evidence‐based guidance for the management of syphilis during pregnancy. The guidance advocates for universal early screening, strengthened health systems to ensure access to free and timely prenatal care, and the integration of effective follow‐up strategies. As early diagnosis and treatment are highly effective in reducing transmission, syphilis screening should begin at the first prenatal visit. While regional protocols vary, at a minimum, screening should be repeated at delivery in countries that have not yet met WHO eradication targets. Benzathine penicillin remains the treatment of choice, with proven efficacy and safety. Additionally, screening and treatment of sexual partners are essential to prevent maternal reinfection and community transmission. Strengthening health systems to support these interventions is fundamental to improving maternal and fetal/neonatal health outcomes and advancing towards global elimination of congenital syphilis worldwide.

Objetivo: generar recomendaciones para la vacunación de la mujer, en las diferentes etapas de su vida, a fin de disminuir la posible variabilidad de su uso actual en Colombia. Materiales y métodos: el grupo desarrollador estuvo conformado por profesionales pertenecientes al área de la salud. Todos los participantes declararon por escrito sus conflictos de interés. Se formularon preguntas clínicas contestables, se hizo la graduación de los desenlaces y la pesquisa de la información se realizó en Medline/PubMed, Embase y Lilacs. La búsqueda también abarcó fuentes de literatura gris y se actualizó el 14 de mayo de 2024 sin restricciones por fecha o idioma. Se implementó la metodología GRADE (Grading of Recommendations Assessment, Development and Evaluation) para establecer la calidad de la evidencia y la fuerza de la recomendación. En virtud de las limitaciones de los estudios recuperados, y especialmente cuando se trató de limitaciones en la aplicabilidad de la evidencia, se acudió a la opinión de expertos. Se realizó consenso formal acorde con la metodología RAND/UCLA (RAND Corporation/Universidad de California en Los Ángeles). Previo a la publicación, el documento fue objeto de revisión por pares. Resultados: se desarrollaron las siguientes recomendaciones: El grupo desarrollador sugiere que las mujeres no inmunes a las paperas, sarampión o rubeola (p. ej., IgG negativo) sean vacunadas durante el periodo preconcepcional. Calidad de la evidencia: baja ⨁⨁◯◯ El grupo desarrollador sugiere que todas las mujeres en periodo preconcepcional se vacunen contra la varicela si no tienen inmunidad natural confirmada (p. ej., anticuerpos IgG negativo para el virus varicela zóster). Calidad de la evidencia: muy baja ⨁◯◯◯ El grupo desarrollador sugiere que las mujeres que viven en regiones endémicas para fiebre amarilla se vacunen durante el periodo preconcepcional si no han sido previamente inmunizadas. Calidad de la evidencia: muy baja ⨁◯◯◯ El grupo desarrollador sugiere vacunar adolescentes y adultas jóvenes con la vacuna para el virus del papiloma humano (VPH), de 3 dosis (0,2 y 6 meses) con el fin de reducir la incidencia y mortalidad por cáncer cervical. Calidad de evidencia: moderada ⨁⨁⨁◯ El grupo desarrollador sugiere que las mujeres gestantes sean inmunizadas contra el tétano, la difteria y la tos ferina durante la gestación, con el objetivo de reducir el riesgo de infección en la madre y el neonato. Calidad de la evidencia: baja ⨁⨁◯◯ El grupo desarrollador sugiere la vacunación contra la influenza a cualquier edad gestacional, con el objetivo de reducir el riesgo de infección en la madre y el neonato hasta los seis meses de edad. Calidad de la evidencia: muy baja ⨁◯◯◯ El grupo desarrollador sugiere la vacunación materna frente al COVID-19 a cualquier edad gestacional, con el objetivo de reducir el riesgo de hospitalización y muerte de la madre y el neonato durante los primeros cuatro meses de vida. Calidad de la evidencia: muy baja ⨁◯◯◯ El grupo desarrollador sugiere la vacunación contra el virus sincitial respiratorio (VSR) en mujeres gestantes, con el objetivo de reducir el riesgo de hospitalización en el neonato. Calidad de la evidencia: muy baja ⨁◯◯◯ El grupo desarrollador sugiere que la mujer adulta mayor se vacune contra el herpes zóster, con el fin de reducir la morbilidad asociada a esta condición. Calidad de la evidencia: moderada ⨁⨁⨁◯ El grupo desarrollador sugiere que la mujer adulta mayor se vacune contra la influenza a fin de reducir la incidencia de infección respiratoria aguda (IRA). Calidad de la evidencia: moderada ⨁⨁⨁◯ El grupo desarrollador sugiere que la mujer adulta mayor se vacune contra el neumococo a fin de reducir la incidencia de neumonía y enfermedad neumocócica invasora. Calidad de la evidencia: baja ⨁⨁◯◯ El grupo desarrollador sugiere que la mujer adulta mayor se vacune contra el VSR a fin de reducir la incidencia de infección respiratoria aguda e infección respiratoria del tracto inferior. Calidad de la evidencia: baja ⨁⨁◯◯ El grupo desarrollador sugiere que la mujer adulta mayor que vive en regiones endémicas para fiebre amarilla se vacune si no ha sido previamente inmunizada. Calidad de la evidencia: muy baja ⨁◯◯◯ Conclusiones: se recomienda la vacunación como estrategia de prevención primaria a lo largo de las diferentes etapas de la vida en la mujer. Dada la calidad de la evidencia y las serias limitaciones en la aplicabilidad de algunos estudios, especialmente en mujeres gestantes, se requieren más investigaciones que evalúen la seguridad y la efectividad de esta intervención en esta etapa de la vida.

Objective: Previous research has identified an association between maternal stress, fetal growth and the expression of glucocorticoid‐related genes in the placenta, particularly 11‐beta hydroxysteroid dehydrogenase‐2 ( HSD11β2 ). However, to date, no studies have simultaneously explored the relationships between maternal stress, placental expression and methylation of HSD11β2 , and fetal cortisol metabolites according to fetal growth. The aim of the present study was to evaluate the association between perceived antenatal maternal stress, the expression and methylation of the placental HSD11β2 gene, fetal cortisol metabolites in amniotic fluid and birth weight. Methods: This nested case–control study, which was part of a large prospective cohort study, was conducted at two maternofetal medicine units in Barcelona, Spain (BCNatal: Hospitals Clinic and Sant Joan de Déu). We enrolled singleton pregnancies and classified neonates as small‐for‐gestational age (SGA) if their birth weight was below the 10 ^th percentile ( n = 343) or as appropriate‐for‐gestational‐age (AGA) controls ( n = 399). The Perceived Stress Scale (PSS) and the State–Trait Anxiety Inventory (STAI) scores were obtained to assess maternal stress and anxiety levels. We analyzed placental HSD11β2 RNA expression ( n = 44 SGA and n = 28 AGA) and DNA methylation levels ( n = 89 SGA and n = 34 AGA), and fetal cortisol metabolites and the activity of metabolizing enzymes in amniotic fluid ( n = 135 SGA and n = 78 AGA) using liquid chromatography‐tandem mass spectrometry. Results: Median maternal perceived stress (PSS, 23 (interquartile range (IQR), 17–28) vs 20 (IQR, 15–26); P < 0.001) and median anxiety state (STAI‐state, 19.0 (IQR, 14.0–29.0) vs 16.0 (IQR, 11.0–24.0); P < 0.001) scores were significantly higher in the SGA group compared with the control group. SGA cases showed lower median placental HSD11β2 RNA expression (Δ Ct, 50.5 (IQR, 21.6–106.0) vs 92.7 (IQR, 62.3–118.0); P = 0.013) with similar DNA methylation levels (mean ± SD, 10.7 ± 3.0% vs 11.0 ± 2.8%; P = 0.648) compared with AGA controls. Analysis of amniotic fluid revealed altered cortisol metabolism in SGA fetuses, with increased median 5α‐tetrahydrocortisol concentration (SGA, 0.09% (IQR, 0.06–0.15%) vs controls, 0.07% (IQR, 0.05–0.11%); P = 0.020) and activity of its related enzyme (5α‐reductase activity in SGA, 0.19% (IQR, 0.14–0.31%) vs controls, 0.17% (IQR, 0.12–0.22%); P = 0.007), together with a decrease in median 6‐hydroxycortisol concentration (SGA, 0.09% (IQR, 0.06–0.11%) vs controls, 0.11% (IQR, 0.08–0.12%); P < 0.001) and activity of its related enzyme (CYP3A7 activity in SGA, 0.19% (IQR, 0.11–0.25%) vs controls, 0.24% (IQR, 0.17–0.33%); P < 0.001). Conclusions: SGA pregnancy is associated with high perceived maternal stress and dysregulated fetoplacental cortisol metabolism. These results deepen our understanding of the pathophysiology of SGA and highlight the potential benefit of intervention to mitigate maternal stress. © 2025 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Objective: To investigate the prognostic value of maternal angiogenic factors in late‐onset small fetuses, alone or in combination with the ultrasound and Doppler parameters currently used for the classification of low‐risk small‐for‐gestational‐age (SGA) fetuses or high‐risk fetal growth restriction (FGR), overall and according to the presence or absence of pre‐eclampsia. Methods: This was a prospective cohort study of women with a singleton pregnancy with a diagnosis of late‐onset fetal smallness (defined as birth weight < 10 ^th centile) and a gestational age of ≥ 34 weeks at delivery. Ultrasound assessment of estimated fetal weight (EFW) and Doppler assessment of uterine artery pulsatility index (UtA‐PI) and cerebroplacental ratio (CPR) were performed every 1–2 weeks. Biochemical analysis of the angiogenic factors placental growth factor (PlGF) and soluble fms‐like tyrosine kinase‐1 (sFlt‐1) in maternal peripheral venous blood samples was performed using enzyme‐linked immunosorbent assay within 1–2 weeks after diagnosis of SGA or FGR. The primary outcome was adverse perinatal outcome, defined as a composite of emergency Cesarean section for non‐reassuring fetal status, metabolic acidosis (umbilical artery pH < 7.0), neonatal unit admission and/or perinatal death. The predictive value of EFW < 3 ^rd centile, Doppler parameters (UtA‐PI > 95 ^th centile and CPR < 5 ^th centile) and sFlt‐1/PlGF ratio > 95 ^th centile, alone or in combination, was assessed using logistic regression analysis in the overall population and stratified by presence or absence of pre‐eclampsia developing at any time before delivery. Results: Among the 602 included cases, 91 (15.1%) developed pre‐eclampsia and 511 (84.9%) did not. In the overall study population, all parameters were associated independently with adverse perinatal outcome: EFW < 3 ^rd centile (adjusted odds ratio (aOR), 2.58 (95% CI, 1.67–4.00)), UtA‐PI > 95 ^th centile (aOR, 1.92 (95% CI, 1.25–2.94)), CPR < 5 ^th centile (aOR, 2.35 (95% CI, 1.46–3.78)) and sFlt‐1/PlGF ratio > 95 ^th centile (aOR, 1.71 (95% CI, 1.09–2.69)). Only sFlt‐1/PlGF ratio > 95 ^th centile was associated independently with adverse perinatal outcome in cases with pre‐eclampsia, whereas in those without pre‐eclampsia, only EFW < 3 ^rd centile and CPR < 5 ^th centile were associated independently with adverse perinatal outcome. In the overall population, the detection rate (DR) and false‐positive rate for adverse perinatal outcome were, respectively: 39.8% (95% CI, 31.7–47.9%) and 16.9% (95% CI, 10.7–23.1%) for sFlt‐1/PlGF ratio > 95 ^th centile alone; 86.8% (95% CI, 83.4–90.2%) and 61.9% (95% CI, 57.1–66.7%) for a combined model of EFW < 3 ^rd centile, UtA‐PI > 95 ^th centile and CPR < 5 ^th centile; 81.3% (95% CI, 77.3–85.3%) and 52.3% (95% CI, 47.1–57.5%) for a combined model of EFW < 3 ^rd centile and sFlt‐1/PlGF ratio > 95 ^th centile; and 88.5% (95% CI, 85.4–91.6%) and 64.5% (95% CI, 59.8–69.2%) for a combined model including all the abovementioned observed parameters. Conclusions: sFlt‐1/PlGF ratio alone had a low predictive value for adverse perinatal outcome, but when combined with EFW, its predictive performance was similar to that of EFW combined with Doppler parameters. Combining sFlt‐1/PlGF ratio with EFW and Doppler criteria achieved the highest DR for adverse perinatal outcome, and additionally, might help to identify imminent pre‐eclampsia in pregnancies complicated by fetal smallness. These findings support the use of angiogenic factors as an additional criterion to those currently used for identifying high‐risk FGR among late‐onset small fetuses, but do not support their use as a standalone biomarker. © 2025 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.