Prevalence of corpus callosum pathology in an unselected population. Should assessment of the corpus callosum be included in the routine 20 weeks scan?

OBJECTIVES: To determine the prevalence of abnormalities of the corpus callosum (AbnCC) in a non-selected population, to propose a systematic screening protocol for AbnCC in all populations through direct assessment, and to describe the follow-up and prognosis of all AbnCC cases diagnosed in our clinical setting. METHODS: This was a retrospective review of the prevalence of AbnCC over 11 years. We included a sagittal assessment of the corpus callosum (CC) in the second-trimester scan. AbnCC was classified into complete agenesis of CC (ACC) and dysgenesis of CC (DCC; including small, partial agenesis, thick and with lipoma). RESULTS: Of the 38,586 second-trimester scans performed during our screening, 43 cases of AbnCC were detected (prevalence of 0.8/1000). Of the AbnCC cases, 10 cases were identified as ACC (29.40%) and 24 as DCC (70.59%). Follow-up investigations showed that in the 43 cases with AbnCC, 76.5% had other associated ultrasound abnormalities, 26.5% had genetic abnormalities, 11.8% had other MRI abnormalities, and 25% of the children had neurodevelopmental delays (8.8% of the total), which were severe in only one case. CONCLUSIONS: AbnCC is found in approximately 0.8/1000 of cases in an unselected population. The findings suggest that systematic and direct assessment of the CC as part of screening ultrasound in the second trimester of gestation should be recommended as a routine practice.

Vascular Grafts with Tailored Stiffness and a Ligand Environment via Multiarmed Polymer Sheath for Expeditious Regeneration.

The bypass graft is the mainstream of surgical intervention to treat vascular diseases. Ideal bypass materials, yet to be developed, require mechanical properties, availability, clinically feasible manufacturing logistics, and bioactivities with precise physicochemical cues defined to guide cell activities for arterial regeneration. Such needs instigated our fabrication of vascular grafts, which consist of coaxial, nanostructured fibers exhibiting a polycaprolactone (PCL) core and a photoclickable, 4-arm thiolated polyethylene glycol-norbornene (PEG-NB) sheath. The graft strength and bioactivity were modulated by the PCL concentration and the peptides (RGD, transforming growth factor ß-1 or TGF-ß1) conjugated to thiol-ene of PEG-NB, respectively. Structural, physical, and mechanical characterizations demonstrated that the fibrous grafts mimicked the key features of the native extracellular matrix, including a crosslinked fiber network for structural stability, viscoelasticity emulating arteries, hydration property, and high porosity for cell infiltration. Meanwhile, these grafts displayed strength and toughness exceeding or meeting surgical criteria. Furthermore, the grafts with higher PCL concentration (3 vs 1.8%) showed thicker fibers, lower porosity and pore size, and increased elastic and storage moduli. Graft bioactivity was determined by the mesenchymal stem cell (MSC) behaviors on the grafts and arterial regeneration in vivo using interposition grafting. Results showed that the cell adhesion and proliferation increased with the RGD density (25 vs 5 mM). After 1 week implantation, all peptide-functionalized PCL/PEG-NB grafts with or without MSC preseeding, as opposed to PCL grafts, showed expeditious endothelial lining, abundant vascular cell infiltration, and matrix production. Compared to RGD grafts, RGD/TGF-ß1 grafts enhanced MSC differentiation into smooth muscle cells in vitro and developed thicker smooth muscle cell layers in vivo. Overall, the versatile porous vascular grafts offer superior properties and tunability for future translation.

Coaxial PCL/PEG-thiol-ene microfiber with tunable physico-chemical properties for regenerative scaffolds.

Tissue regeneration requires scaffolds that exhibit mechanical properties similar to the tissues to be replaced while allowing cell infiltration and extracellular matrix production. Ideally, the scaffolds' porous architecture and physico-chemical properties can be precisely defined to address regenerative needs. We thus developed techniques to produce hybrid fibers coaxially structured with a polycaprolactone core and a 4-arm, polyethylene glycol thiol-norbornene sheath. We assessed the respective effects of crosslink density and sheath polymer size on the scaffold architecture, physical and mechanical properties, as well as cell-scaffold interactions in vitro and in vivo. All scaffolds displayed high elasticity, swelling and strength, mimicking soft tissue properties. Importantly, the thiol-ene hydrogel sheath enabled tunable softness and peptide tethering for cellular activities. With increased photopolymerization, stiffening and reduced swelling of scaffolds were found due to intra- and inter-fiber crosslinking. More polymerized scaffolds also enhanced the cell-scaffold interaction in vitro and induced spontaneous, deep cell infiltration to produce collagen and elastin for tissue regeneration in vivo. The molecular weight of sheath polymer provides an additional mechanism to alter the physical properties and biological activities of scaffolds. Overall, these robust scaffolds with tunable elasticity and regenerative cues offered a versatile and effective platform for tissue regeneration.

Etiology and Prognosis of Severe Ventriculomegaly Diagnosed at Late Gestation.

OBJECTIVES: We sought to assess the causes and outcomes of severe VM diagnosed de novo after 24 weeks of gestation where a mid-trimester anomaly scan was described as normal. METHODS: Multicenter retrospective study of five European fetal medicine centers. The inclusion criteria were normal anatomy at the mid-trimester scan, uni/bilateral finding of posterior ventricle measuring ≥ 15 mm after 24 weeks with neonatal and postnatal pediatric and/or neurological assessment data. RESULTS: Of 74 potentially eligible cases, 10 underwent termination, the outcome was missing in 19 cases and there was 1 neonatal death. Therefore, 44 formed the study cohort with a median gestation at diagnosis of 32 + 0 weeks (25 + 6 - 40 + 5). VM was unilateral in five cases. Agenesis of the corpus callosum (ACC) and grade III/IV intraventricular hemorrhage (IVH) accounted for 14 cases each. ACC was isolated in 9 fetuses. Obstructive abnormalities included 5 arachnoid and 1 cavum velum interpositum cyst. Four fetuses had an associated suspected or confirmed genetic condition, 2 congenital infections, 1 abnormal cortical development and the etiology was unknown in 3/44. Postnatal assessment at median 20 months (3 - 96) showed 22/44 (50 %) normal, 7 (16 %) mildly abnormal and 15 (34 %) severely abnormal neurodevelopmental outcomes. CONCLUSION: One half of babies with severe VM diagnosed after 24 weeks have normal infant outcome with ACC and IVH representing the most common causes. Etiology is the most important factor affecting the prognosis of fetuses with severe VM diagnosed at late gestation.

Initial experience with non-invasive prenatal testing of cell-free DNA for major chromosomal anomalies in a clinical setting.

OBJECTIVE: To evaluate non-invasive prenatal testing (NIPT) of cell-free DNA (cfDNA) as a screening method for major chromosomal anomalies (CA) in a clinical setting. METHODS: From January to December 2013, Panorama™ test or Harmony™ prenatal test were offered as advanced NIPT, in addition to first-trimester combined screening in singleton pregnancies. RESULTS: The cohort included 333 pregnant women with a mean maternal age (MA) of 37 years who underwent testing at a mean gestational age of 14.6 weeks. Eighty-four percent were low-risk pregnancies. Results were provided in 97.3% of patients at a mean reporting time of 12.9 calendar days. Repeat sampling was performed in six cases and results were obtained in five of them. No results were provided in four cases. Four cases of Down syndrome were detected and there was one discordant result of Turner syndrome. We found no statistical differences between commercial tests except in reporting time, fetal fraction and MA. The cfDNA fraction was statistically associated with test type, maternal weight, BMI and log ßhCG levels. CONCLUSIONS: NIPT has the potential to be a highly effective screening method for major CA in a clinical setting.

Caso iconográfico número 16: lipoma de cuerpo calloso / Illustrated case number 16: Corpus callosum lipoma

No disponible

Prenatal invasive testing: a 13-year single institution experience.

OBJECTIVES: To analyze trends in screening and invasive prenatal diagnosis over a 13-year period in relation to changes in the national prenatal screening policy. METHODS: Fetal karyotypes obtained following 11 045 prenatal invasive procedures between January 1999 and December 2011 were retrospectively reviewed. Referral indications were classified as medical and non-medical (anxiety). The number of tests per relevant chromosomal abnormalities (CA) detected in both groups adjusted for indication was calculated. RESULTS: A total of 414 CA were detected (3.8%), 355 of which were considered clinically significant. The percentage of invasive procedures has declined from 49% to 12%, although cases referred by anxiety have increased from 22% to 55%. A total of 3129 invasive procedures did not have any medical indication (28%) and 13 relevant CA (0.42%) were found in this group. In this low-risk series, the index "number of invasive testing needed to detect 1 relevant CA" adjusted for indication was 241. CONCLUSIONS: Changes in our national prenatal policy through this 13-year period show an increasing efficiency of prenatal detection of CA. However, despite the intensifying screening policies, low-risk pregnant women show a growing demand for prenatal invasive testing and a baseline risk for cytogenetic abnormality of 1/241.

Cumulative sum plots and retrospective parameters in first-trimester ductus venosus quality assurance.

OBJECTIVE: This study aimed to evaluate the application of two quality assurance methods to the ductus venosus pulsatility index (DVPI), as a first-trimester aneuploidy marker, including retrospective assessment of distribution parameters and cumulative sum (CUSUM) plots. METHODS: The DVPI was measured in 14 444 singleton fetuses at 11+0 to 13+6 weeks in two Fetal Medicine centers during a 4-year period. Sonologist-specific quality assurance distribution parameters, previously described for nuchal translucency, were assessed: the median multiples of the median (MoM), the logarithmic standard deviation of DVPI MoMs and the weekly DVPI percent decrease. Quality assurance results were compared between median MoMs and MoM-based CUSUM plots. RESULTS: When sonologist-specific DVPI distribution parameters were retrospectively applied for quality assurance, a 1.0 median MoM, a 0.1 median logarithmic standard deviation and a 3.4 median weekly DVPI drop percentage were observed. CUSUM plots showed good agreement with 0.9-1.1 MoMs range for median MoM, in the assessment of sonologist-specific performances. CONCLUSION: Retrospective and prospective DVPI quality assurance methods appear to be applicable to DVPI at 11+0 to 13+6 weeks. Its use should be encouraged if DVPI is to be added to first-trimester Down syndrome or cardiac defects screening.

Updated reference ranges for the ductus venosus pulsatility index at 11-13 weeks.

OBJECTIVE: To update the reference ranges for the ductus venosus pulsatility index (DVPI) at 11+0 to 13+6 gestational weeks. METHODS: DVPI was calculated in 14,444 singleton fetuses at 11+0 to 13+6 weeks in two Fetal Medicine Centers, during a 4-year period. Using previously described medians, DVPI evolution was assessed both over the study period on a yearly basis and over gestation, grouping fetuses according to 5-mm crown-rump length (CRL) ranges. Weighted DVPI medians, the 5th and 95th percentiles and distribution parameters for unaffected and trisomy 21 fetuses were newly calculated. RESULTS: A significant DVPI multiple of the median decrease was observed over both the study period (p < 0.01) and over gestation (p < 0.01) using previous medians, in the two centers. Newly calculated weighted medians were lower than those previously described, decreasing with CRL. Distribution parameters calculated using the new medians were different from those previously described. CONCLUSION: DVPI reference ranges were lower than those previously reported and decreased with CRL. Updated medians and distribution parameters should be considered to include the DVPI as a Gaussian marker in trisomy 21 screening and for quality control purposes.

Control de calidad en el cribado prenatal de aneuploidías / Quality control in prenatal screening for aneuploidy

Un aspecto esencial e imprescindible de los programas de cribado prenatal es el control de calidad. En este sentido, contrariamente a lo que ocurre en el ámbito del laboratorio clínico, donde las pruebas analíticas están sometidas a estrictos controles de calidad para determinar y confirmar su fiabilidad, en el campo de la medicina fetal y más concretamente en el ámbito de la ecografía prenatal, el concepto de evaluación de la calidad y la certificación solo recientemente ha sido objeto de interés. En todo programa de cribado prenatal, aunque la tasa de detección del síndrome de Down (SD) sigue siendo una prioridad y un indicador de su efectividad, este parámetro no puede ser utilizado como un marcador fiable de la calidad del mismo, fundamentalmente debido a la baja prevalencia de dicha condición. Los esfuerzos en el control de calidad del cribado prenatal de aneuploidías deben incluir indicadores más fiables, realistas y de aplicación individualizada. Este artículo pretende revisar y clarificar los conceptos fundamentales en el ámbito del control de calidad en el cribado prenatal de aneuploidías y propone estrategias para mejorar su fiabilidad (AU)

Quality control is an essential aspect of prenatal screening programs. In this respect, contrary to what happens in the field of the clinical laboratory, where the analytical tests are submitted to strict quality controls to determine and to confirm their reliability in the field of the foetal medicine, and more specifically in the área of prenatal ultrasound, the concept of quality assessment and certification has only recently been a subject of interest. In any prenatal screening program, although the detection rate of Down’s Síndrome (SD) remains being a priority and an indicator of its efficiency, this parameter cannot be used as a reliable marker of its quality, mainly due to the low prevalence of this condition. Efforts in the quality control of prenatal screening for aneuploidy should include more reliable, realistic and individualised applications. This article aims to review and clarify the key concepts in the field of quality control in prenatal screening for aneuploidy and proposes strategies to improve reliability (AU)

Prenatal Diagnosis of Chromosome Abnormalities: A 13-Year Institution Experience.

OBJECTIVE: To analyze trends in screening and invasive prenatal diagnosis of chromosome abnormalities (CA) over a 13-year period and correlate them to changes in the national prenatal screening policy. METHODS: We retrospectively reviewed Down syndrome (DS) screening tests and fetal karyotypes obtained by prenatal invasive testing (IT) in our fetal medicine unit between January 1999 and December 2011. RESULTS: A total of 24,226 prenatal screening tests for DS and 11,045 invasive procedures have been analyzed. Over a 13-year period, utilization of non-invasive screening methods has significantly increased from 57% to 89%. The percentage of invasive procedures has declined from 49% to 12%, although the percentage of IT performed for maternal anxiety has increased from 22% to 55%. The percentage of detected CA increased from 2.5% to 5.9%. Overall, 31 invasive procedures are needed to diagnose 1 abnormal case, being 23 procedures in medical indications and 241 procedures in non-medical indications. CONCLUSIONS: Our experience on screening and invasive prenatal diagnostic practice shows a decrease of the number of IT, with a parallel decline in medical indications. There is an increasing efficiency of prenatal screening program to detect CA. Despite the increasing screening policies, our population shows a growing request for prenatal IT. The a priori low risk population shows a not negligible residual risk for relevant CA. This observation challenges the current prenatal screening strategy focused on DS; showing that the residual risk is higher than the current cut-off used to indicate an invasive technique.

Valoración de la translucencia nucal y anatomía fetal en la ecografía de 11-13+6 semanas: técnica bidimensional frente a tridimensional / Assessment of nuchal translucency and foetal anatomy in the 11-13.6 weeks ultrasound: two-dimensional versus three-dimensional technique

Introducción. se valora la posibilidad de evaluar la anatomía fetal y la medición de la translucencia nucal (TN) a partir del estudio diferido de un volumen capturado mediante ecografía tridimensional (3D). Objetivo. comparar los resultados obtenidos mediante la exploración ecográfica bidimensional (2D) y 3D. Método. estudio prospectivo realizado en 100 gestaciones únicas, que acuden para cribado de aneuploidías entre la 11 y 13,6 semanas. Se practica ecografía 2D vía abdominal por un primer explorador (E1), con estudio anatómico (definido en base a un score anatómico), valoración de TN (según criterios de la Fetal Medicine Foundation) y mapa Doppler color (ductus venoso y vasos umbilicales). El mismo explorador (E1) captura un volumen fetal total 3D vía abdominal, con y sin Doppler color. Los volúmenes 3D se valoran en diferido mediante navegación multiplanar por dos exploradores (E1, E2). Resultados. la medición del CRL pudo hacerse por ambos exploradores en el 100% de los casos en 2D y 3D, sin diferencias significativas entre ambos. La TN pudo valorarse en el 100% de los casos mediante la ecografía 2D, y en el 63 y el 48% mediante ecografía 3D en E1 y E2, respectivamente. Los porcentajes de valoración de la anatomía son inferiores mediante la exploración 3D, aunque alcanza el 90-100% en estructuras como cabeza, tórax, abdomen, estómago y extremidades. No se encuentran diferencias en el tiempo de exploración entre ambas técnicas. Se demuestra que a mayor experiencia del explorador, menor es el tiempo de análisis en diferido, aunque este tiempo se estabiliza a partir de 20 volúmenes analizados (curva de aprendizaje). Conclusión. la obtención de un solo volumen fetal total 3D vía transabdominal entre las 11 y las 13,6 semanas permite una valoración en diferido de la anatomía básica y de la TN, aunque en cifras inferiores al 2D(AU)

Introduction. An evaluation is made of the possibility of assessing foetal anatomy and measuring nuchal translucency (NT) from the deferred study of the volume captured using three-dimensional (3D) ultrasound. Objective. To compare the results obtained by the two-dimensional (2D) and 3D ultrasound examination. Method. A prospective study performed on 100 single pregnancies, who came for aneuploidy screening between 11-13.6 weeks gestation. A 2D abdominal ultrasound was performed by a first examiner (E1), with an anatomical study (defined based on an anatomy score), an NT evaluation (based on criteria of the Foetal Medicine Foundation) and a colour Doppler map (ductus venosus and umbilical vessels. The same examiner (E1) captured a total foetal volume by abdominal 3D, with and without colour Doppler. The 3D volumes were assessed by two examiners (E1 and E2) in deferred mode using multiplanar navigation. Results. Measurement of the crown-rump length (CRL) could be made in 2D and 3D by both examiners in 100% of cases, with no significant differences between them. The NT could be assessed in 100% of cases using 2D ultrasound, and in 63% and 48% of cases using 3D ultrasound by E1 and E2, respectively. The anatomy assessment percentages were lower with 3D, although they reached 90-100% in structures such as the head, thorax, abdomen, stomach and limbs. There were no differences in the examination times between the techniques. It showed that the more experienced the examiner, the lower the time of deferred analysis; although this time was established from 20 volumes analysed (learning curve). Conclusion. The obtaining a single total foetal volume by trans-abdominal 3D ultrasound between 11-13.6 weeks allows an assessment to be made of the basic anatomy and the NT, although in percentages lower than in 2D(AU)

Rapid aneuploidy testing versus traditional karyotyping in amniocentesis for certain referral indications.

OBJECTIVE: (1) To determine the suitability of replacing full karyotype analysis with quantitative fluorescent polymerase chain reaction (QF-PCR) for prenatal diagnosis in amniotic fluid samples obtained by amniocentesis. (2) To evaluate an indication-based classification of cases at risk of missing clinically relevant chromosomal disorders by QF-PCR. METHODS: We reviewed all fetal karyotypes obtained by amniocentesis between January 2004 and December 2008. We compared the cytogenetic findings obtained through conventional karyotype with those that would have been theoretically obtained using QF-PCR. RESULTS: Of the 4007 karyotypes obtained, 110 abnormal karyotypes were found (2.8%). Out of these, 30 (27%) were chromosomal abnormalities (CA) which would not have been detected by PCR alone. These included 16 cases (53%) predicted to confer no increased risk, 9 (30%) predicted to have a low risk, and 5 (17%) with an uncertain or high risk of fetal abnormality. A policy of QF-PCR alone would have identified 80 of 85 (94%) clinically significant CA. When QF-PCR shows a normal result, the overall residual risk is 0.75% for any CA and 0.12% for a clinical significant CA. CONCLUSION: In our population, a policy of QF-PCR alone would miss 0.12% clinically relevant CA. QF-PCR directed to common aneuploidies can be considered as an economically and clinically acceptable prenatal diagnosis policy, offering full karyotype only for specific indications.

Diagnóstico prenatal en el segundo trimestre de displasia torácica asfixiante / Prenatal diagnosis in the second trimester of asphyxiating thoracic dysplasia

Describimos un caso de diagnóstico prenatal de síndrome de Jeune. Debido a su baja incidencia, es excepcional realizar el diagnóstico de este síndrome a las 21 semanas de gestación en una paciente de riesgo bajo. La displasia torácica asfixiante o síndrome de Jeune es una displasia esquelética hereditaria de carácter autonómico recesivo. El diagnóstico prenatal se puede realizar por ecografía; este síndrome se caracteriza por tórax pequeño, costillas cortas, anormalidades pélvicas, braquimelia rizomélica, y anomalías renales y hepáticas, entre otras. En nuestro caso, el diagnóstico prenatal fue confirmado con la necropsia

A case of prenatal diagnosis of Jeune’s syndrome is described. Because the incidence of this syndrome is low, diagnosis in the 21st week of pregnancy is exceptional. Jeune’s syndrome, or asphyxiating thoracic dysplasia, is a skeletal dysplasia with autosomal recessive inheritance. Prenatal diagnosis can be established by ultrasonographic findings of a small thorax, short ribs, pelvic abnormalities, rhizomelic brachymelia, and renal and liver anomalies, among others. In the present case, the prenatal diagnosis was confirmed at necropsy (AU)

Three-dimensional yolk and gestational sac volume. A prospective study of prognostic value.

OBJECTIVE: To evaluate the relative prognostic value of ultrasound findings during the first-trimester scan by univariate and logistic regression analysis in a group of asymptomatic women. STUDY DESIGN: A total of 125 asymptomatic pregnant women with a singleton conceptus, concordance between menstrual age and crown-rump length, and documented fetal activity, 25 for each gestational age between 6 and 10 weeks, were enrolled in the study and underwent a transvaginal sonographic examination. The following data were collected: yolk sac mean diameter and volume, gestational sac mean diameter and volume, fetal heart rate, maternal age, gestational age and presence of a retrochorial hematoma. The outcome variable was abortion, defined as pregnancy loss at any time up to 20 weeks' gestation. Normograms were constructed for volumes, mean diameters and fetal heart rate. Receiver-operator characteristic curves were performed in order to dichotomize maternal and gestational age. Univeriate analysis was performed by Fisher's exact test. Logistic regression was performed to test the relationship between independent variables and pregnancy outcome. RESULTS: In univariate analysis, the variables significantly associated with spontaneous abortion were maternal age > 34 years, yolk sac volume outside the 5th to 95th percentile, gestational sac volume < the 5th percentile and fetal heart rate outside the 5th to 95th percentile. In regression analysis only maternal age > 34 years, gestational sac mean diameter < 5th percentile and fetal heart rate outside the 5th to 95th percentile were significant in predicting abortion. CONCLUSION: Our data suggest that new three-dimensional parameters are of no clinical benefit in the prediction of abortion in nonbleeding, first-trimester pregnancy, when conventional sonographic parameters are used.

Measurement of nuchal translucency as a single strategy in trisomy 21 screening: should we use any other marker?

OBJECTIVE: To evaluate the role of nuchal translucency thickness as a single marker in screening for trisomy 21 at 10-16 weeks' gestation. METHODS: From December 1996 to October 2001, nuchal translucency was measured in 11,281 consecutive early second trimester fetuses referred to our unit for prenatal care and delivery. Scans were performed by eight experienced ultrasonographers, under strict methodological criteria. RESULTS: Chromosomal abnormalities were found in 118 cases (52 trisomy 21). Using nuchal translucency greater than the 95th centile as a cut-off, the overall detection rate was 71.2% with a specificity of 95.4%, and a positive predictive value of 14%. In the trisomy 21 selected group, detection rate, specificity, and positive predictive value for nuchal translucency were 92.3%, 95.4%, and 8.5%, respectively. The detection rate of trisomy 21 reached 100% when nuchal translucency was measured between 10 and 14 weeks' gestation, maintaining the same specificity. CONCLUSION: Early second trimester nuchal translucency measurement can achieve prenatal detection rates of trisomy 21 greater than 95% with a 5% false-positive rate. With a detection rate so high, the benefits of using additional markers may be less than previously considered. Although maternal age, other sonographic or Doppler markers, and maternal serum biochemistry might play a role in prenatal strategies to detect fetal chromosomal abnormalities, the high detection rate of trisomy 21 fetuses using nuchal translucency as a single parameter suggests that early nuchal translucency measurement between 10 and 14 weeks' gestation can be a simple screening strategy for this condition.

References intervals for fetal biometrical parameters.

OBJECTIVE: To establish normal reference intervals for biparietal diameter, head circumference, abdominal circumference, and length of femur, a cross-sectional study. STUDY DESIGN: Five hundred singleton fetuses for each week at gestations between 23 and 41 weeks with a total of 9500 fetuses. Antenatal ultrasound measurements from all consecutive pregnant women referred to the ultrasound unit for scanning of fetal condition are prospectively entered in a data bank. For the purpose of this study, sonographic measurements were collected retrospectively and each fetus contributed just one value to the reference sample. RESULTS: The mean curve of the four biometrical parameters varied with gestational age, with flattening of the curves at the end of gestation and increased width of normal ranges with increasing gestational age. Maximal weekly increases occurred at 24 weeks' gestation for head circumference, abdominal circumference, and length of femur and at 26 weeks' gestation for biparietal diameter. The four biometrical parameters, however, showed 50% increases in size at 33 weeks' gestation. CONCLUSIONS: These fetal size reference intervals are clinically relevant and can be used for populations with epidemiological features and distribution of neonatal birth weights similar to our data.

Effect of surgical menopause and Paget's disease of bone on the isomerization of type I collagen carboxyterminal telopeptide: evolution after antiresorptive therapy.

The objective of this study was to analyze the effect of surgical menopause and Paget's disease of bone, as well as the influence of therapy, on the isomerization of the carboxyterminal telopeptide of type I collagen (CTX). Fourteen women who had undergone surgical menopause and had begun hormone replacement therapy (HRT) after surgery were recruited. Results for these women were compared with those of 29 patients with Paget's disease of bone treated with tiludronate (400 mg/day) for 3 months, and with those of a group of 21 healthy premenopausal women (control group I). In addition, 14 healthy individuals with an age range similar to that of the pagetic patients (control group II) were included in the study. Urine samples were analyzed for levels of nonisomerized and beta-isomerized CTX (alpha-CTX and beta-CTX). Biochemical determinations were performed 3 months after surgical menopause and after 3 and 9 months of HRT, and at baseline, and 1 and 6 months after tiludronate treatment in the pagetic patients. The average levels of alpha-CTX and beta-CTX were higher in patients than in controls. In patients after surgical menopause, because of their greater increase of beta-CTX, the alpha-CTX/beta-CTX ratio was lower than that of control group I (0.881 +/- 0.3 vs 1.515 +/- 0.8; P < 0.05). In contrast, at baseline, pagetic patients showed marked increases in alpha-CTX levels, resulting in a higher alpha-CTX/beta-CTX ratio than that of control group II (2.879 +/- 1.3 vs 0.96 +/- 0.25; P < 0.0001). The average percent decrease in both markers after therapy was similar in both conditions (-60% for alpha-CTX and -44% for beta-CTX after 3 months of HRT in the surgical menopause group, vs -66% for alpha-CTX and -41% for beta-CTX in the pagetic group, 1 month after finishing tiludronate therapy; P, NS), resulting in a significant decrease of the alpha-CTX/beta-CTX ratio in pagetic patients (2.879 +/- 1.3 vs. 1.614 +/- 0.8; P < 0.001). In conclusion, surgical menopause is associated with a decrease in the urinary alpha-CTX/beta-CTX ratio because of the higher increase in the beta-CTX level after menopause. Pagetic patients show an increase in this ratio, compared with the control value, and the ratio decreases after bisphosphonate treatment. The response to therapy was similar in both conditions, with a comparable decrease of both markers. These findings show how bone markers may contribute to the understanding of pathophysiologic mechanisms in bone diseases.