Revisiting MOMS criteria for prenatal repair of spina bifida: upper gestational-age limit should be raised and assessment of prenatal motor function rather than anatomical level improves prediction of postnatal function.

OBJECTIVES: To determine if the lower-extremity neurological motor function level in fetuses with open spina bifida deteriorates within the 4-week interval between a first prenatal motor assessment at around 22 weeks of gestation and a second evaluation, prior to 'late' prenatal surgery, defined as surgery at 26-28 weeks and, in certain situations, up to 30 weeks, and to assess the association between prenatal presurgical motor-function level, anatomical level of the lesion and postnatal motor-function level. METHODS: This was a two-center cohort study of 94 singleton fetuses with open spina bifida which underwent percutaneous repair using the skin-over-biocellulose for antenatal fetoscopic repair (SAFER) technique between December 2016 and January 2022. All women underwent two prenatal systematic ultrasound evaluations, approximately 4 weeks apart, with the second one being performed less than 1 week before surgery, and one postnatal evaluation via physical examination within 2 months of birth. Motor-function classification was from spinal level T12 to S1, according to key muscle function. Each leg was analyzed separately; in case of discrepancy between the two legs, the worst motor-function level was considered for analysis. Motor-function-level evaluations were compared with each other and with the anatomical level as observed on ultrasound. Independent predictors of a postnatal reduction in motor-function level were assessed using a logistic regression model. RESULTS: Prenatal motor-function level was assessed at a median gestational age of 22.5 (interquartile range (IQR), 20.7-24.3) and 26.7 (IQR, 25.4-27.3) weeks, with a median interval of 4.0 (IQR, 2.4-6.0) weeks. The median gestational age at surgery was 27.0 (IQR, 25.9-27.6) weeks and the postnatal examination was at median age of 0.8 (IQR, 0.3-5.4) months. There was no significant difference in motor-function level between the two prenatal evaluations (P = 0.861). We therefore decided to use the second prenatal evaluation for comparison with postnatal motor function and anatomical level. Overall, prenatal and postnatal motor function evaluations were significantly different from the anatomical level (preoperative assessment, P = 0.0015; postnatal assessment, P = 0.0333). Comparing prenatal with postnatal motor-function level, we found that 87.2% of babies had similar or improved motor function compared with that prior to prenatal surgery. On logistic regression analysis, lower anatomical level of defect and greater difference between anatomical level and prenatal motor-function level were identified as independent predictors of postnatal motor function (odds ratio, 0.237 (95% CI, 0.095-0.588) (P = 0.002) and 3.44 (95% CI, 1.738-6.813) (P < 0.001), respectively). CONCLUSIONS: During a 4-week interval between first ultrasound evaluation and late fetal surgical repair of open spina bifida, motor function does not change significantly, suggesting that late repair, ≥ 26 weeks, does not impact negatively on motor-function outcome. Compared with the anatomical level of the lesion, preoperative neurological motor-function assessment via ultrasound is more predictive of postnatal motor function, and should be included in preoperative counseling. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Biocellulose patch technique for fetoscopic repair of open spina bifida in twin pregnancy.

OBJECTIVES: Twin pregnancy is currently an exclusion criterion for prenatal repair of open spina bifida (OSB). The main objective of this study was to report on our experience of treating twin pregnancies with OSB using the skin-over-biocellulose for antenatal fetoscopic repair (SAFER) technique. We also discuss reconsideration of the current exclusion criteria for fetal OSB repair. METHODS: Eight fetuses with OSB from seven twin pregnancies underwent successful prenatal repair. Six pregnancies were dichorionic diamniotic with only one twin affected, and one was monochorionic diamniotic with both twins affected. Percutaneous fetoscopy was performed under CO2 insufflation of the sac of the affected twin. Neurosurgical repair was performed using a biocellulose patch to protect the placode, with the skin sutured to hold the patch in place, with or without a myofascial flap. Neurodevelopment was assessed using the pediatric evaluation of disability inventory scale in babies older than 6 months of adjusted age, whereas the Alberta scale was used for babies younger than 6 months of adjusted age. RESULTS: All 14 fetuses were liveborn and none required additional repair. Gestational age at surgery ranged from 27.3 to 31.1 weeks, and gestational age at birth ranged from 31.6 to 36.0 weeks. Four out of eight affected twins developed sepsis, but had a good recovery. No sequela of prematurity was found in any of the unaffected twins. Short-term neurodevelopment was normal in all evaluated unaffected twins (5/5) and in all but one affected twins (7/8). In the affected group, only one baby required ventriculoperitoneal shunt placement. CONCLUSIONS: Prematurity is frequent after fetal surgery, and the risk is increased in twin pregnancy. Nevertheless, prenatal surgery using the SAFER technique is feasible, with low risk to both twins and their mother when performed by a highly experienced team. Long-term cognitive assessment of the unaffected twin is needed. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Prevalence of supratentorial anomalies assessed by magnetic resonance imaging in fetuses with open spina bifida.

OBJECTIVES: To determine the prevalence of brain anomalies at the time of preoperative magnetic resonance imaging (MRI) assessment in fetuses eligible for prenatal open spina bifida (OSB) repair, and to explore the relationship between brain abnormalities and features of the spinal defect. METHODS: This was a retrospective cross-sectional study, conducted in three fetal medicine centers, of fetuses eligible for OSB fetal surgery repair between January 2009 and December 2019. MRI images obtained as part of the presurgical assessment were re-evaluated by two independent observers, blinded to perinatal results, to assess: (1) the type and area of the defect and its anatomical level; (2) the presence of any structural central nervous system (CNS) anomaly and abnormal ventricular wall; and (3) fetal head and brain biometry. Binary regression analyses were performed and data were adjusted for type of defect, upper level of the lesion (ULL), gestational age (GA) at MRI and fetal medicine center. Multiple logistic regression analysis was performed in order to identify lesion characteristics and brain anomalies associated with a higher risk of presence of abnormal corpus callosum (CC) and/or heterotopia. RESULTS: Of 115 fetuses included, 91 had myelomeningocele and 24 had myeloschisis. Anatomical level of the lesion was thoracic in seven fetuses, L1-L2 in 13, L3-L5 in 68 and sacral in 27. Median GA at MRI was 24.7 (interquartile range, 23.0-25.7) weeks. Overall, 52.7% of cases had at least one additional brain anomaly. Specifically, abnormal CC was observed in 50.4% of cases and abnormality of the ventricular wall in 19.1%, of which 4.3% had nodular heterotopia. Factors associated independently with higher risk of abnormal CC and/or heterotopia were non-sacral ULL (odds ratio (OR), 0.51 (95% CI, 0.26-0.97); P = 0.043), larger ventricular width (per mm) (OR, 1.23 (95% CI, 1.07-1.43); P = 0.005) and presence of abnormal cavum septi pellucidi (OR, 3.76 (95% CI, 1.13-12.48); P = 0.031). CONCLUSIONS: Half of the fetuses assessed for OSB repair had an abnormal CC and/or an abnormal ventricular wall prior to prenatal repair. The likelihood of brain abnormalities was increased in cases with a non-sacral lesion and wider lateral ventricles. These findings highlight the importance of a detailed preoperative CNS evaluation of fetuses with OSB. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Percutaneous fetoscopic spina bifida repair: effect on ambulation and need for postnatal cerebrospinal fluid diversion and bladder catheterization.

OBJECTIVE: A trial comparing prenatal with postnatal open spina bifida (OSB) repair established that prenatal surgery was associated with better postnatal outcome. However, in the trial, fetal surgery was carried out through hysterotomy. Minimally invasive approaches are being developed to mitigate the risks of open maternal-fetal surgery. The objective of this study was to investigate the impact of a novel neurosurgical technique for percutaneous fetoscopic repair of fetal OSB, the skin-over-biocellulose for antenatal fetoscopic repair (SAFER) technique, on long-term postnatal outcome. METHODS: This study examined descriptive data for all patients undergoing fetoscopic OSB repair who had available 12- and 30-month follow-up data for assessment of need for cerebrospinal fluid (CSF) diversion and need for bladder catheterization and ambulation, respectively, from eight centers that perform prenatal OSB repair via percutaneous fetoscopy using a biocellulose patch between the neural placode and skin/myofascial flap, without suture of the dura mater (SAFER technique). Univariate and multivariate logistic regression analyses were used to examine the effect of different factors on need for CSF diversion at 12 months and ambulation and need for bladder catheterization at 30 months. Potential cofactors included gestational age at fetal surgery and delivery, preoperative ultrasound findings of anatomical level of the lesion, cerebral lateral ventricular diameter, lesion type and presence of bilateral talipes, as well as postnatal findings of CSF leakage at birth, motor level, presence of bilateral talipes and reversal of hindbrain herniation. RESULTS: A total of 170 consecutive patients with fetal OSB were treated prenatally using the SAFER technique. Among these, 103 babies had follow-up at 12 months of age and 59 had follow-up at 30 months of age. At 12 months of age, 53.4% (55/103) of babies did not require ventriculoperitoneal shunt or third ventriculostomy. At 30 months of age, 54.2% (32/59) of children were ambulating independently and 61.0% (36/59) did not require chronic intermittent catheterization of the bladder. Multivariate logistic regression analysis demonstrated that significant prediction of need for CSF diversion was provided by lateral ventricular size and type of lesion (myeloschisis). Significant predictors of ambulatory status were prenatal bilateral talipes and anatomical and functional motor levels of the lesion. There were no significant predictors of need for bladder catheterization. CONCLUSION: Children who underwent prenatal OSB repair via the percutaneous fetoscopic SAFER technique achieved long-term neurological outcomes similar to those reported in the literature after hysterotomy-assisted OSB repair. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Peri-operative management of percutaneous fetoscopic spina-bifida repair: a descriptive review of five cases from the United Kingdom, with focus on anaesthetic implications.

We present a case-based review of the first five percutaneous fetoscopic in-utero spina bifida repair procedures undertaken in the UK. Our focus is on implications of anaesthesia and analgesia for the mother and fetus, provision of uterine relaxation and fetal immobilisation while providing conditions conducive to surgical access. Minimising risks for fetal acidosis, placental and fetal hypoperfusion, maternal and fetal sepsis and maternal fluid overload were the foremost priorities. We discuss optimisation strategies undertaken to ensure fetal and maternal well-being under anaesthesia, shortcomings in the current approach, and possible directions for improvement.

Learning curves of open and endoscopic fetal spina bifida closure: systematic review and meta-analysis.

OBJECTIVE: The Management of Myelomeningocele Study (MOMS) trial demonstrated the safety and efficacy of open fetal surgery for spina bifida aperta (SBA). Recently developed alternative techniques may reduce maternal risks without compromising the fetal neuroprotective effects. The aim of this systematic review was to assess the learning curve (LC) of different fetal SBA closure techniques. METHODS: MEDLINE, Web of Science, EMBASE, Scopus and Cochrane databases and the gray literature were searched to identify relevant articles on fetal surgery for SBA, without language restriction, published between January 1980 and October 2018. Identified studies were reviewed systematically and those reporting all consecutive procedures and with postnatal follow-up ≥ 12 months were selected. Studies were included only if they reported outcome variables necessary to measure the LC, as defined by fetal safety and efficacy. Two authors independently retrieved data, assessed the quality of the studies and categorized observations into blocks of 30 patients. For meta-analysis, data were pooled using a random-effects model when heterogeneous. To measure the LC, we used two complementary methods. In the group-splitting method, competency was defined when the procedure provided results comparable to those in the MOMS trial for 12 outcome variables representing the immediate surgical outcome, short-term neonatal neuroprotection and long-term neuroprotection at ≥ 12 months of age. Then, when raw patient data were available, we performed cumulative sum analysis based on a composite binary outcome defining successful surgery. The composite outcome combined four clinically relevant variables for safety (absence of extreme preterm delivery < 30 weeks, absence of fetal death ≤ 7 days after surgery) and efficacy (reversal of hindbrain herniation and absence of any neonatal treatment of dehiscence or cerebrospinal fluid leakage at the closure site). RESULTS: Of 6024 search results, 17 (0.3%) studies were included, all of which had low, moderate or unclear risk of bias. Fetal SBA closure was performed using standard hysterotomy (11 studies), mini-hysterotomy (one study) or fetoscopy by either exteriorized-uterus single-layer closure (one study), percutaneous single-layer closure (three studies) or percutaneous two-layer closure (one study). Only outcomes for standard hysterotomy could be meta-analyzed. Overall, outcomes improved significantly with experience. Competency was reached after 35 consecutive cases for standard hysterotomy and was predicted to be achieved after ≥ 57 cases for mini-hysterotomy and ≥ 56 for percutaneous two-layer fetoscopy. For percutaneous and exteriorized-uterus single-layer fetoscopy, competency was not reached in the 81 and 28 cases available for analysis, respectively, and LC prediction analysis could not be performed. CONCLUSIONS: The number of cases operated is correlated with the outcome of fetal SBA closure, and the number of operated cases required to reach competency ranges from 35 for standard hysterotomy to ≥ 56-57 for minimally invasive modifications. Our observations provide important information for institutions looking to establish a new fetal center, develop a new fetal surgery technique or train their team, and inform referring clinicians, potential patients and third parties. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Curvas de aprendizaje del cierre de la espina bífida fetal mediante cirugía abierta y endoscópica: revisión sistemática y metaanálisis OBJETIVO: El ensayo del Estudio sobre la Gestión del Mielomeningocele (MOMS, por sus siglas en inglés) demostró la seguridad y eficacia de la cirugía fetal abierta para la espina bífida aperta (EBA). Las técnicas alternativas recientemente desarrolladas pueden reducir los riesgos de la madre sin comprometer los efectos neuroprotectores del feto. El objetivo de esta revisión sistemática fue evaluar la curva de aprendizaje (CA) de diferentes técnicas de cierre de la EBA fetal. MÉTODOS: Se realizaron búsquedas en las bases de datos de MEDLINE, Web of Science, EMBASE, Scopus y Cochrane, así como en la literatura gris, para identificar artículos relevantes sobre cirugía fetal para la EBA, sin restricción de idioma, publicados entre enero de 1980 y octubre de 2018. Se examinaron sistemáticamente los estudios identificados y se seleccionaron los que informaban de todos los procedimientos consecutivos y con seguimiento postnatal ≥12 meses. Los estudios se incluyeron sólo si informaban sobre las variables de resultado necesarias para medir la CA, definidas por la seguridad y la eficacia para el feto. Dos autores recuperaron los datos de forma independiente, evaluaron la calidad de los estudios y clasificaron las observaciones en bloques de 30 pacientes. Para el metaanálisis, los datos se agruparon mediante un modelo de efectos aleatorios cuando fueron heterogéneos. Para medir la CA, se usaron dos métodos complementarios. En el método de división de grupos, la competencia se definió cuando el procedimiento proporcionó resultados comparables a los del ensayo MOMS para 12 variables de resultados que representaban el resultado quirúrgico inmediato, la neuroprotección neonatal a corto plazo y la neuroprotección a largo plazo a ≥12 meses de edad. Luego, cuando se dispuso de los datos brutos de los pacientes, se realizó un análisis de suma acumulada basado en un resultado binario compuesto que definió el éxito de la cirugía. El resultado compuesto combinó cuatro variables clínicamente relevantes en cuanto a la seguridad (ausencia de parto pretérmino extremo <30 semanas; ausencia de muerte fetal a ≤7 días después de la cirugía) y eficacia (reducción de la hernia del rombencéfalo y ausencia de cualquier tratamiento neonatal de dehiscencia o derrame de líquido cefalorraquídeo en el lugar del cierre). RESULTADOS: De los 6024 resultados de la búsqueda, se incluyeron 17 (0,3%) estudios, todos ellos con un riesgo de sesgo bajo, moderado o incierto. El cierre de la EBA fetal se realizó mediante histerotomía estándar (11 estudios), mini histerotomía (un estudio) o fetoscopia, ya fuera mediante el cierre exteriorizado del útero de una sola capa (un estudio), el cierre percutáneo de una sola capa (tres estudios) o el cierre percutáneo de dos capas (un estudio). Sólo se pudieron metaanalizar los resultados de la histerotomía estándar. En general, los resultados mejoraron significativamente con la experiencia. Se alcanzó la competencia después de 35 casos consecutivos para la histerotomía estándar y se predijo que se alcanzaría después de ≥57 casos para la mini histerotomía y ≥56 para la fetoscopia percutánea de dos capas. En el caso de las fetoscopias percutánea y exteriorizada del útero de una sola capa, no se alcanzó la competencia en los 81 y 28 casos disponibles para el análisis, respectivamente, y no se pudo realizar el análisis de predicción de la CA. CONCLUSIONES: El número de casos operados está correlacionado con el resultado del cierre de la EBA fetal, y el número de casos operados necesarios para alcanzar la competencia estuvo entre 35 para la histerotomía estándar y ≥56-57 para las operaciones con mínima agresividad. Las observaciones realizadas proporcionan información importante para las instituciones que buscan establecer un nuevo centro fetal, desarrollar una nueva técnica de cirugía fetal o entrenar a su equipo, e informar a los médicos que remiten a especialistas a los posibles pacientes y a terceros. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Type III interferon (IFN-lambda) antagonizes the antiviral activity of interferon-alpha in vitro.

Type III interferons (IFN-lambda) are the most recently discovered members of IFN family. Synergism between different IFN types is well established, but for type I and type III IFNs no conclusive evidence has been reported so far. Possible synergism/antagonism between IFN-alpha and IFN-lambda in the inhibition of virus replication (EMCV, WNV lineage 1 and 2, CHIKV and HSV-1), and in the activation of intracellular pathways of IFN response (MxA and 2'-5' OAS) was evaluated in different cell lines (Vero E6, A549 and Wish cells). The antiviral potency of IFN-lambda1 and -l2 was lower than that of IFN-alpha. When IFN-alpha and -lambda were used together, the Combination Index (CI) for virus inhibition was greater than 1 virtually for all virus/host cell systems, indicating antagonistic effect. Antagonism between IFN-alpha and -l was also observed for the induction of mRNA for both MxA and 2'-5'OAS. Elucidating the interplay between IFN-alpha and -lambda may help to better understand innate defence mechanisms against viral infections, including the molecular mechanisms underlying the influence of IL-28B polymorphisms in the response to HCV and other viral infections.

Thyroxine binding to members and non-members of the serine protease inhibitor family.

Partition of T4 to plasma proteins is classically attributed only to TBGC approximately/= 70%), transthyretin (approximately/= 15%) and albumin (approximately/= 10%), based on zone electrophoresis. Since TBG migration spans the alpha1 and alpha2 regions, and since HDL, which have alpha1 migration, transport approximately/= 4% of circulating T4, other alpha-globulins could bind T4 and "contaminate" the TBG area. Hence, we determined the association of [125I]T4 to TBG and, for comparison, to transthyretin and albumin. Sera from 50 normolipidemic individuals were equilibrated with [125I] T4 and analyzed by both zone electrophoresis and radioimmunoprecipitation with specific antisera. Transthyretin-T4 or albumin-T4 bindings as assessed by the two methods agreed, while TBG-T4 did not, because other alpha-globulins carrying T4 with low affinity co-migrated with TBG. Some, but not all, of these alpha-globulins belong to the same superfamily of TBG and also bind steroid hormones.

Abnormalities of GH secretion in a young girl with Floating-Harbor syndrome.

We present a 9.1-year-old girl of Calabrian (Italy) ancestry, with clinical features (cranio-facial dysmorphism, short stature with delayed bone age and speech delay) suggesting the diagnosis of Floating-Harbor syndrome (FHS). Physical examination showed: height 113.9 cm (-2.9 SD), with a parent's target of 156.2 cm (+1.0 SD), weight 20.7 kg, BMI 16.0 (-0.04 SD), and many phenotypic abnormalities: long eyelashes, large bulbous nose with broad nasal bridge, short philtrum, moderately broad mouth, tooth folding and malocclusion, posteriorly rotated ears, low posterior hair line, short neck, clinodactyly of the 5th finger and hyperextensible finger joints. Diffused hyperpigmentation and hypertrichosis with sporadic pubic terminal hairs, but neither clitoromegaly nor other signs of hyperandrogenism and/or precocious puberty, were observed (T1, P1). Carpal bone evaluation showed a delayed bone age (TW2: 5-5/10, - 3.6 yr) and the statural age/bone age ratio was 1.1. Other dysmorphic syndromes were excluded on the basis of clinical evidence, also evaluated by a computer-assisted search (P.O.S.S.U.M. version 3.5, 1992). Analysis of chromosome 22 by the FISH method, using specific probes Cos29 and Tuple1, excluded microdeletions in the region 22q11.2, typical of Velo-cardio-facial syndrome. In this case, we report the impairment of serum GH responsiveness (GH baseline values: 0.2-1.9 ng/ml) to the administration of oral 150 microg clonidine [peak 4.7 ng/ml, normal values (nv)>10 ng/ml] and oral 4 mg dexamethasone (8.1 ng/ml, nv>10 ng/ml). Moreover, the evaluation of spontaneous 24-h GH secretion (Carmeda AB, Stockholm, Sweden) showed low mean GH levels (1.75 ng/ml, nv>3.0 ng/ml), with a maximum sleep-related peak of 2.8 ng/ml. Serum IGF-1 values were in the low-normal range (80-176 ng/ml, nv 133-626 ng/ml). While in FHS the cranio-facial features minimize with advancement of age, the impairment of growth velocity is permanent and results in severe dwarfism. In our case, treatment with recombinant GH (0.10 U/kg/day), administered by a needle-free device, induced a dramatic increase of growth velocity, increasing the height from -2.8 to -1.9 SD after 18 months, thus indirectly confirming a role of GH deficiency in the pathogenesis of FHS dwarfism.

Usefulness of L-carnitine, a naturally occurring peripheral antagonist of thyroid hormone action, in iatrogenic hyperthyroidism: a randomized, double-blind, placebo-controlled clinical trial.

Old studies in animals and unblinded studies in a few hyperthyroid patients suggested that L -carnitine is a periferal antagonist of thyroid hormone action at least in some tissues. This conclusion was substantiated by our recent observation that carnitine inhibits thyroid hormone entry into the nucleus of hepatocytes, neurons, and fibroblasts. In the randomized, double-blind, placebo-controlled 6-month trial reported here, we assessed whether 2 or 4 g/d oral L-carnitine were able to both reverse and prevent/minimize nine hyperthyroidism- related symptoms. We also evaluated changes on nine thyroid hormone-sensitive biochemical parameters and on vertebral and hip mineral density (bone mineral density). Fifty women under a fixed TSH-suppressive dose of L -T(4) for all 6 months were randomly allocated to five groups of 10 subjects each. Group 0 associated placebo for 6 months; groups A2 and A4 started associating placebo (first bimester), substituted placebo with 2 or 4 g/d carnitine (second bimester), and then returned to the association with placebo. Groups B2 and B4 started associating 2 and 4 g/d carnitine for the first two bimesters, and then substituted carnitine with placebo (third bimester). Symptoms and biochemical parameters worsened in group 0. In group A, symptoms and biochemical parameters worsened during the first bimester, returned to baseline or increased minimally during the second bimester (except osteocalcin and urinary OH-proline), and worsened again in the third bimester. In group B, symptoms and biochemical parameters (except osteocalcin and urinary OH-proline) did not worsen or even improved over the first 4 months; they tended to worsen in the third bimester. In both the A and B groups, the two doses of carnitine were similarly effective. At the end of the trial, bone mineral density tended to increase in groups B and A (B > A). In conclusion, L-carnitine is effective in both reversing and preventing symptoms of hyperthyroidism and has a beneficial effect on bone mineralization. Because hyperthyroidism depletes the body deposits of carnitine and since carnitine has no toxicity, teratogenicity, contraindications and interactions with drugs, carnitine can be of clinical use.

Re-evaluation of the thyroxine binding to human plasma lipoproteins using three techniques.

Using gel filtration chromatography (GFC), we found that human VLDL, LDL and HDL transport approximately 0.03, 0.2 and 3% of plasma T4. As T4 could dissociate from carriers during GFC, we evaluated [125I]T4 transport to lipoproteins (Lp) in 50 normolipidemic and euthyroid subjects by GFC and 2 independent methods: zone electrophoresis (ZE) and radioimmunoprecipitation (RIP). At GFC, VLDL+LDL transported less T4 (approximately 0.3%) than either ZE (approximately 1.3%) or RIP (approximately 1.5-2.0%). In contrast, GFC values for the HDL (approximately 3%) were close to the RIP values (approximately 3.5%), but lower than ZE (approximately 8.5%) because of partial co-migration with TBG. In conclusion, GFC underestimates T4 binding to VLDL and LDL, which, indeed, is of the same magnitude as binding of some steroid hormones to CBG and SHBG. Hence, the anti-atherosclerotic effects of T4 resulting from binding to the LDL should be greater than anticipated based on GFC data.