Peter M. Doubilet

Long-term Assessment of a Multidisciplinary Approach to Thyroid Nodule Diagnostic Evaluation

The diagnostic evaluation of patients with thyroid nodules is imprecise. Despite the benefits of fine‐needle aspiration (FNA), most patients who are referred for surgery because of abnormal cytology prove to have benign disease. Recent technologic and procedural advances suggest that this shortcoming can be mitigated, although few data confirm this benefit in unselected patients.

Use and Misuse of the Term “Cost Effective” in Medicine

There has been mounting pressure on the medical profession in recent years to stem the rise in national health care expenditures. One result of that pressure has been the popularization of the term...

Maternal infection, fetal inflammatory response, and brain damage in very low birth weight infants

Echolucent images (EL) of cerebral white matter, seen on cranial ultrasonographic scans of very low birth weight newborns, predict motor and cognitive limitations. We tested the hypothesis that markers of maternal and feto-placental infection were associated with risks of both early (diagnosed at a median age of 7 d) and late (median age = 21 d) EL in a multi-center cohort of 1078 infants <1500 ×g. Maternal infection was indicated by fever, leukocytosis, and receipt of antibiotic; feto-placental inflammation was indicated by the presence of fetal vasculitis (i.e. of the placental chorionic plate or the umbilical cord). The effect of membrane inflammation was also assessed. All analyses were performed separately in infants born within 1 h of membrane rupture (n= 537), or after a longer interval (n= 541), to determine whether infection markers have different effects in infants who are unlikely to have experienced ascending amniotic sac infection as a consequence of membrane rupture. Placental membrane inflammation by itself was not associated with risk of EL at any time. The risks of both early and late EL were substantially increased in infants with fetal vasculitis, but the association with early EL was found only in infants born ≥1 after membrane rupture and who had membrane inflammation (adjusted OR not calculable), whereas the association of fetal vasculitis with late EL was seen only in infants born <1 h after membrane rupture (OR = 10.8;p= 0.05). Maternal receipt of antibiotic in the 24 h just before delivery was associated with late EL only if delivery occurred <1 h after membrane rupture (OR = 6.9;p= 0.01). Indicators of maternal infection and of a fetal inflammatory response are strongly and independently associated with EL, particularly late EL.

Usefulness of Ultrasonography in the Management of Nodular Thyroid Disease

Thyroid nodules are a common diagnostic challenge encountered in clinical medicine. Approximately 4% to 7% of adults have palpable thyroid nodules, and up to 70% have thyroid nodules visible on ultrasonography, many of which are less than 1 cm in diameter (1-5). Fine-needle aspiration biopsy is the standard diagnostic test for evaluating a palpable thyroid nodule in euthyroid patients. Previous studies have shown that the diagnostic accuracy of fine-needle aspiration biopsy is improved with ultrasonography guidance compared with palpation alone (6-9). In addition, ultrasonography guidance is required for aspiration of nonpalpable thyroid nodules (10-12). The objective of our study was to determine whether the routine use of ultrasonography in all patients with suspected thyroid nodules changed clinical management compared with palpation alone. Methods Patients The study sample consisted of all patients referred to the Brigham and Womens Hospital dual-discipline (endocrinology and radiology) Thyroid Nodule Clinic (Boston, Massachusetts) for suspected nodular thyroid disease or suspected recurrent thyroid cancer between October 1995 and March 1997. Clinicians were instructed to refer patients with suspected or diagnosed nodular thyroid disease and a normal serum thyrotropin level to the Thyroid Nodule Clinic. If patients had a suppressed thyrotropin level and were not taking thyroid hormone, a radionuclide scan was suggested. The clinic visit included thyroid ultrasonography performed by a radiologist, an evaluation by an endocrinologist, and ultrasonography-guided fine-needle aspiration biopsy of all nodules measuring at least 1 cm in maximum diameter (up to a maximum of four nodules). A cutoff of 1 cm was selected on the basis of recommendations in the literature (13). For patients seen more than once, only the initial visit was analyzed. Measurements Medical records were reviewed for the specialty of the referring clinician, the referring clinicians examination of the thyroid before referral, and the indication for referral. Sonography was performed by using 5- to 10-MHz transducers. Nodules were measured in three dimensions. Fine-needle aspiration was performed with a 25-gauge needle. Ultrasonography guidance was used to confirm placement of the needle in the nodule or to direct sampling into solid portions of partially cystic nodules. Four to six passes were made per nodule. The needles were rinsed and pooled in a single vial containing CytoLyt solution (CytoLyt Corp., Boxborough, Massachusetts). Two ThinPrep slides (Cytyc Corp., Marlborough, Massachusetts) were stained by using a modified Papanicolaou method and were read by a cytopathologist at the Brigham and Womens Hospital as benign, atypical, suspicious for a follicular or Hrthle cell neoplasm, suspicious or positive for papillary cancer, or nondiagnostic. Aspirates were considered nondiagnostic if they contained fewer than six groups of benign follicular cells. The atypical category was applied to cases in which a mild degree of cellular or architectural atypia precluded a benign diagnosis but was insufficient for a suspicious or positive diagnosis. Cytology reports were reviewed for all patients who had fine-needle aspiration biopsy, and histologic reports were reviewed for all patients who had surgery. Two endocrinologists reviewed the charts to compare the referring physicians findings on thyroid physical examination with the ultrasonography findings. If a discrepancy existed between the referring physicians clinical thyroid examination and the number of nodules requiring fine-needle aspiration biopsy based on ultrasonography ( 1 cm), ultrasonography was considered to have altered the clinical management. Role of the Funding Sources The funding sources had no role in the collection, analysis, and interpretation of the data or in the decision to submit the paper for publication. Results Characteristics of the Study Group A total of 223 patients (203 women and 20 men [mean age, 46.3 15.3 years]) were evaluated at the Thyroid Nodule Clinic between October 1995 and March 1997. Sixty-one percent were referred by primary care physicians, 37% were referred by endocrinologists, and 2% were referred by surgeons. The indication for referral was abnormal findings on thyroid physical examination in 173 of 223 patients (78%); 114 were referred for a suspected solitary nodule, 33 were referred for diffuse or asymmetric goiter, and 26 were referred for multinodular goiter (Table 1). Ultrasonography-guided fine-needle aspiration biopsy was performed on 209 nodules in 156 patients. Sixty-seven patients had no aspirations, 112 had one aspiration, and 44 had two or more aspirations. Table 1. Indication for Referral to the Thyroid Nodule Clinic in 223 Patients Sonographic Findings Ultrasonography revealed solitary nodules in 33% of patients, a multinodular goiter (>1 nodule on ultrasonography) in 50%, and no nodules in 17% (excluding those with a history of thyroid cancer). Ultrasonography findings in the 173 patients referred for abnormal findings on thyroid physical examination are given in Table 2. Table 2. Sonographic Findings in 173 Patients Referred to the Thyroid Nodule Clinic for Abnormal Results on Physical Examination Management of Nodular Thyroid Disease Ultrasonography changed management in 44% (50 of 114) of the patients referred for a solitary nodule on physical examination. In 27 patients, an additional nonpalpable nodule at least 1 cm in diameter was found on ultrasonography and more than one nodule required aspiration. Eighteen patients had no nodules, and 5 patients had only small nodules (<1 cm); therefore, despite the results of the physical examination, no aspiration was required. For the remaining 64 patients referred for a solitary nodule (46 with a solitary nodule 1 cm and 18 with multiple nodules but only one nodule 1 cm), clinical management was not affected because the palpated nodule was the only nodule that was at least 1 cm in diameter on ultrasonography. Among the 33 patients referred for a diffuse or asymmetric goiter, 55% (18 of 33) had one or more nodules at least 1 cm in diameter on ultrasonography, which suggests that the examining physician recognized an abnormality but could not detect a discrete nodule. Among the 26 patients referred for a multinodular goiter, 5 did not require an aspiration based on the ultrasonography findings and 21 required one or more aspirations for discrete nodules at least 1 cm in diameter. In summary, ultrasonography altered clinical management in 109 of the 173 patients (63%) referred for abnormal findings on physical examination. It was needed for guidance of nonpalpable nodules that were at least 1 cm in diameter in 66 patients (27 referred for a solitary nodule with additional nodules 1 cm on ultrasonography, 21 referred for a multinodular goiter, and 18 referred for a diffuse or asymmetric goiter with discrete nodules 1 cm on ultrasonography) and documented no nodules that were at least 1 cm in diameter in 43 patients. In the 48 patients referred for other indications, ultrasonography helped 1) evaluate growth in patients with previous benign cytologic findings, 2) direct sampling of lymph nodes in patients with thyroid cancer, 3) direct sampling of nonpalpable nodules found incidentally on other radiology studies, and 4) screen for nodules in patients with previous exposure to radiation. Cytologic Findings after Fine-Needle Aspiration In the 153 patients with no history of thyroid cancer who had fine-needle aspiration, 130 of the 205 nodules aspirated (63%) were benign. Seven nodules (3%), all confirmed histologically, were positive for papillary cancer. Nine (4%) were suspicious for papillary cancer. Five of these (56%) were histologically confirmed as papillary cancer, and 2 were benign. One patient with 2 suspicious nodules sought a second opinion and was lost to follow-up. Seventeen nodules (8%) were suspicious for follicular or Hrthle cell neoplasm, of which 9 were excised; 1 was a follicular carcinoma and the others were benign. Nine nodules (4%) were characterized as atypical. Of these, 2 were found to be benign after surgery. Thirty-three nodules (16%), of which 13 were more than 50% cystic, had nondiagnostic cytologic characteristics. In 1 patient, surgery for papillary carcinoma in 1 nodule revealed papillary carcinoma in a second nodule whose cytologic characteristics were nondiagnostic. The occurrence of malignancy was similar in patients with solitary nodules and those with multiple nodules. Cancer was found in 4 of 60 patients with solitary nodules (6.7%) and 8 of 90 patients with multiple nodules (8.9%). In 4 of the 12 patients who received a diagnosis of thyroid cancer, the malignant nodule was not palpated by the referring physician. One patient was referred for a solitary palpable nodule, which was benign, but a nonpalpable malignant nodule in the contralateral lobe was detected on ultrasonography. In another patient, who was referred for follow-up of a benign nodule, a second nonpalpable nodule was found to be malignant. The malignant nodule was also nonpalpable in the other 2 patients who had either a multinodular or diffuse goiter on the referring clinicians examination. Fine-needle aspiration biopsies of 4 nonpalpable lymph nodes in the 3 patients with a history of thyroid cancer were all positive for recurrent papillary cancer. Discussion We routinely use ultrasonography and ultrasonography-guided fine-needle aspiration in patients referred to our Thyroid Nodule Clinic for suspected thyroid nodules. Almost half of the patients referred for a solitary nodule on physical examination (a group previously not thought to benefit from ultrasonography) were found to have multiple nodules, and many (27 of 48) required additional aspiration of a nonpalpable nodule. More than 50% of patients (18 of 33) with suspected diffuse or asymmetric goiter had discrete nodules requiring fi

Can Color Doppler Sonography Aid in the Prediction of Malignancy of Thyroid Nodules

Objective. To determine whether color Doppler interrogation of a thyroid nodule can aid in the prediction of malignancy. Methods. We obtained color Doppler images of thyroid nodules undergoing sonographically guided fine‐needle aspiration. The color Doppler appearance of each nodule was graded from 0 for no visible flow through 4 for extensive internal flow. The size, sonographic appearance, results of fine‐needle aspiration, and surgical pathologic findings, if available, were recorded for each nodule. Results. There were 254 nodules sampled, of which 32 were malignant (all confirmed at surgery) and 177 were benign. Fourteen (43.8%) of the 32 malignant nodules were color type 4, compared with only 26 (14.7%) of the 177 benign nodules (P = .0004, Fisher exact test). Thirteen (40.1%) of the 32 malignant nodules were solid, as were 18 (10.2%) of the 177 benign nodules (P = .006, Fisher exact test). Among solid nodules, the prevalence of malignancy was greater when the nodule was hypervascular (13 [41.9%] of 31) than when the color type was less than 4 (11 [14.7%] of 77; P = .004, Fisher exact test). Conclusions. Solid hypervascular thyroid nodules have a high likelihood of malignancy (nearly 42% in our series). The color characteristics of a thyroid nodule, however, cannot be used to exclude malignancy, because 14% of solid nonhypervascular nodules were malignant

Natural History of Benign Solid and Cystic Thyroid Nodules

Context Although benign thyroid nodules are common, we know relatively little about their natural history. Contribution This observational study from a single tertiary care facility used repeated ultrasonography to show that benign thyroid nodules typically increase in volume over a 3- to 5-year period. Solid nodules grew more than cystic nodules, and only 1 of 74 reaspirated nodules was malignant. Implications Nodule growth alone does not predict malignancy. The Editors Thyroid nodules are present in nearly 50% of adults, increasing in prevalence with age (1). The evaluation of thyroid nodules that measure 1 cm or greater in diameter typically includes a screening measure of serum thyroid-stimulating hormone (TSH) levels and fine-needle aspiration (FNA). Most FNA results are benign (90% to 95%), and follow-up examinations are advised. Recommendations include periodic clinical examinations or ultrasonography, with or without suppressive l-thyroxine therapy (1, 2). Nodules that increase in size during follow-up are often regarded as suspicious for malignancy, and repeated FNA or surgery is advised (3-6). Data supporting these recommendations are limited, however, as few reports have evaluated thyroid nodule growth using the most sensitive technique, high-resolution ultrasonography. Furthermore, criteria defining nodule growth are inconsistent; some guidelines use an increase in maximal diameter of greater than 50%, while others suggest an increase in maximal diameter greater than 5 mm or an increase in calculated volume greater than 15% (5-10). We used ultrasonography of thyroid nodules to determine the natural history of cytologically benign thyroid nodules over a 1-month to 5-year follow-up period. Methods We retrospectively reviewed the records of all patients referred to the dual-discipline Thyroid Nodule Clinic at Brigham and Womens Hospital, Boston, Massachusetts, for evaluation of nodular thyroid disease between 1995 and 2000. All patients referred to the clinic underwent ultrasonography of the thyroid by a radiologist and ultrasonography-guided FNA of nodules measuring 1 cm or greater in maximal diameter by an endocrinologist. All ultrasonography evaluations were adequate for review and interpretation. All patients with benign cytology on initial FNA were advised to schedule follow-up ultrasonography 9 to 12 months later. Repeated FNA was performed on the follow-up visit at the discretion of the endocrinologist, usually because of nodule growth. The study sample included all patients with nodules with benign cytologic results on the initial visit who returned for follow-up ultrasonography within the 5-year period. Thyroid ultrasonography was performed by one of three radiologists using a 5- to 15-MHz transducer. The length, width, and depth of each nodule were reported, and each nodule was classified as solid, less than 25% cystic, 25% to 50% cystic, 50% to 75% cystic, or greater than 75% cystic. Nodule volume was calculated by using the formula for a rotational ellipsoid (length width depth /6) (7, 11, 12). Ultrasonography-guided FNA was performed with a 25-gauge needle (three to four aspirations per nodule), and specimens were processed by using the Thin-Prep technique (Cytyc Corp., Boxborough, Massachusetts). All slides were read by a cytopathologist at Brigham and Womens Hospital. Specimens were considered benign when six or more groups of benign follicular cells (each group containing 15 cells) were identified without atypical features. Repeated ultrasonographies were performed, and findings were directly compared with the previous images. Change in nodule size over the interval between examinations was assessed by using three criteria: 1) change in maximal diameter greater than 50% [7, 8, 12, 13]; 2) change in maximal diameter of 3 mm or more; 3) change in calculated volume of 15% or more (11, 14). The latter two criteria are defined by established inaccuracy rates for each method (11, 15). The Investigational Review Board of Brigham and Womens Hospital granted permission to perform this review. Descriptive statistics are presented according to nodule or patient as appropriate. The main outcome for the single-variable and multivariable predictive models was nodule growth, defined as an increase in volume of 15% or greater. Single-variable and multivariable mixed-effects logistic regression was used to predict growth, while accounting for the correlation structure in the data where some patients had more than one nodule (16). Potential predictors were the time between examinations, cystic content (solid, <25% cystic, 25% to 50% cystic, 50% to 75% cystic, or >75% cystic), TSH level (mIU/L), l-thyroxine use, age, and sex. Unadjusted and adjusted odds ratios and 95% CIs were calculated. Time to growth was determined by using life-table methods. Data were analyzed by using SAS software, version 8.2 (SAS Institute, Inc., Cary, North Carolina). The funding sources had no role in the design, conduct, or reporting of the study or the decision to publish the manuscript. Results A total of 1009 patients were examined in the Thyroid Nodule Clinic between 1995 and 2000, and 1358 nodules were biopsied. On initial FNA, 854 nodules (in 700 patients) measured 1 cm or greater in maximal diameter with benign cytologic results. Two hundred sixty-eight patients (38%) with 330 benign thyroid nodules (39%) returned for follow-up ultrasonography, with a mean interval of 20 months (range, 1 to 65 months) between examinations (Appendix Figure). The baseline demographic and ultrasonography characteristics of these 268 patients and their nodules were similar to those of the 432 patients who did not return for follow-up (Table 1). Table 1. Demographic and Ultrasonography Characteristics of Patients with a Benign Thyroid Nodule 1 cm in Maximal Diameter Who Returned for Follow-up Ultrasonography as Recommended Compared with Those Who Did Not Change in nodule size over each patients follow-up period was assessed by three methods to facilitate comparison with previous studies. With use of a greater than 50% change in maximal diameter, 14 nodules (4%) were determined to have increased in size upon repeated ultrasonography. With evaluating change in maximal diameter of 3 mm or greater or change in calculated volume (cm3) of 15% or greater, 86 nodules (26%) and 129 nodules (39%), respectively, were determined to have increased in size on follow-up ultrasonography. The time interval between examinations was significantly correlated with nodule growth (r = 0.22; P < 0.001). Table 2 shows mixed-models logistic regression analysis for prediction of thyroid nodule growth (volume change 15%). Time between examinations and lower cystic content remained statistically significant predictors of growth in the final multivariable model. Each year, the background odds of growth increased by 50%. The estimated median time to achieve volume growth of 15% or greater was 35 months (95% CI, 29 to 41 months). The estimated proportion with growth was 53% (CI, 46% to 61%) at 3 years and 89% (CI, 81% to 97%) at 5 years using life-table methods. The patients age, sex, baseline serum TSH concentration, or l-thyroxine use did not predict nodule growth. Table 2. Single-Variable Predictors and Final Multivariable Model To Predict Thyroid Nodule Growth (Volume Increase 15%) Sixty-one patients underwent repeated FNA at the time of the second ultrasonography. The nodules in this group were larger on initial examination (2.7 cm vs. 2.3 cm; P = 0.001) and had increased in volume by an average of 69% during follow-up compared with 14% in those nodules not rebiopsied (P < 0.001). Patient characteristics were similar except for a longer interval between examinations (28 months vs. 18 months) and younger age (43 years vs. 48 years) noted among the rebiopsied group. One of the 74 repeated FNA samples suggested a follicular neoplasm, and the remainder were benign. The nodule was removed; it was a poorly differentiated papillary carcinoma. It had enlarged from 10.1 cm3 to 18.1 cm3 in volume (an 80% increase) over 38 months. Discussion We used ultrasonography to assess the natural history of 330 benign thyroid nodules measuring 1 cm or more in maximal diameter followed for a mean period of 20 months. Although the 268 patients (with 330 nodules) represent only 39% of the benign nodules seen in the Brigham and Womens Hospital Thyroid Nodule Clinic between 1995 and 2000, they appear to be representative of the whole group with respect to demographic and nodule characteristics. Using the most rigorous criteria ( 15% increase in volume), we documented growth in 39% of benign thyroid nodules during follow-up, which indicates that many such nodules grow. Consistent with our findings, Brander and colleagues (10) found that 35% of benign nodules increased in size over 4.9 to 5.6 years. However, the criteria for growth were not defined, and minimal data on repeated FNA were provided (10). Similarly, Papini and colleagues (15) documented an increase in mean nodule volume among patients in the control group of a 5-year randomized study that assessed the efficacy of l-thyroxine suppression therapy for nodular goiter. Our results also support previous conclusions that more cystic nodules are less likely to grow compared with nodules with a greater solid component (5). Current opinion suggests that increasing nodule size has modest but significant power for predicting thyroid cancer (2). Kuma and colleagues found malignancy in 26% of previously unbiopsied nodules that increased in size over a 10- to 30-year period (5). A follow-up study 2 years later reported a malignancy rate of 4.5% among nodules that were previously found to be benign on FNA and subsequently grew (although no definition of growth was provided) (6). In our study, only 1 of 74 rebiopsied nodules was malignant on repeated FNA biopsy. Although only 22% of nodules seen in follow-up were rebiopsied, this group had s

A randomized, double-blind trial of a gonadotropin releasing-hormone agonist (leuprolide) with or without medroxyprogesterone acetate in the treatment of leiomyomata uteri *

A randomized, double-blind study was performed on 16 women to compare the efficacy of daily subcutaneous (SC) injections of leuprolide acetate (LA; TAP Pharmaceuticals, North Chicago, IL) plus oral placebo tablets (group A, n = 7) with SC LA plus oral medroxyprogesterone acetate (The Upjohn Company, Kalamazoo, MI; group B, n = 9) in the treatment of leiomyomata uteri. Patients in group A had a significant reduction in uterine size from a pretreatment volume of 601 +/- 62 cm3 (mean +/- standard error) to a mean uterine volume of 294 +/- 46 cm3 at 24 weeks of therapy (P less than 0.01). Group B patients had a reduction in uterine volume from 811 +/- 174 cm3 to 688 +/- 154 cm3, which was not statistically significant. However, only one patient in group B experienced hot flashes, whereas six patients in group A had this symptom (P less than 0.01). Both groups demonstrated significant increases in mean hemoglobin concentrations, hematocrits, and serum iron levels at 24 weeks of therapy compared with pretreatment levels.

Changes in intracardiac blood flow velocities and right and left ventricular stroke volumes with gestational age in the normal human fetus: a prospective Doppler echocardiographic study.

We used Doppler echocardiography to quantitate the changes in intracardiac blood flow velocities and right and left ventricular stroke volumes in 80 normal human fetuses from 19 to 40 weeks gestation. Blood flow velocity spectra across the aortic, pulmonary, tricuspid, and mitral valves were digitized to obtain peak velocities (m/sec) and flow velocity integrals. Aortic and pulmonary diameters were measured at valve level from two-dimensional echocardiographic images and cross-sectional area was calculated assuming a circular orifice. Ventricular stroke volume was calculated as the product of the cross-sectional area of a great vessel and the flow velocity integral through that vessel. The pulmonary arterial and aortic diameters increased linearly with gestational age (r = .82, r = .84), and pulmonary arterial diameter consistently exceeded aortic diameter. There was a positive relationship between stroke volume and gestational age: stroke volume increased exponentially from 0.7 ml at 20 weeks to 7.6 ml at 40 weeks for the right ventricle (r = .87) and from 0.7 ml at 20 weeks to 5.2 ml at 40 weeks for the left ventricle (r = .91). Similar results were obtained for right and left ventricular and combined cardiac outputs. In 44% of the fetuses it was possible to quantitate both right and left ventricular stroke volumes. There was a close correlation between right and left ventricular stroke volumes in these fetuses (r = .96) and right ventricular stroke volume exceeded left ventricular stroke volume by 28%.(ABSTRACT TRUNCATED AT 250 WORDS)

Management of asymptomatic ovarian and other adnexal cysts imaged at US: Society of Radiologists in Ultrasound Consensus Conference Statement.

The Society of Radiologists in Ultrasound convened a panel of specialists from gynecology, radiology, and pathology to arrive at a consensus regarding the management of ovarian and other adnexal cysts imaged sonographically in asymptomatic women. The panel met in Chicago, Ill, on October 27-28, 2009, and drafted this consensus statement. The recommendations in this statement are based on analysis of current literature and common practice strategies, and are thought to represent a reasonable approach to asymptomatic ovarian and other adnexal cysts imaged at ultrasonography.

White matter disorders of prematurity: Association with intraventricular hemorrhage and ventriculomegaly

OBJECTIVES Because intraventricular hemorrhage (IVH) often precedes the development of sonographically defined white matter damage (WMD) in very preterm infants, we sought to identify the IVH characteristics that predict WMD. HYPOTHESES We evaluated variations on the null hypothesis that infants with IVH are no more likely than infants without IVH to have WMD. These variations dealt with characteristics of the IVH (presence or absence of ventriculomegaly) or characteristics of the WMD (size, localization, and laterality). METHODS A total of 1605 infants weighing 500 to 1500 g at birth between January 1991 and December 1993 underwent standardized cranial ultrasound studies with 6 standard coronal and 5 sagittal views at postnatal days 1 to 3, 7 to 10, and at 3 to 8 weeks. RESULTS A total of 129 (8%) infants had WMD, either an echodensity alone (n = 59), an echolucency alone (n = 18), or both (n = 52). In analyses that controlled for gestational age, IVH was associated with a fivefold to ninefold increased risk of WMD regardless of size, laterality, or extent of lesions (P </=.0005). Compared with infants with neither IVH nor ventriculomegaly, infants with both were at 18- to 29-fold greater risk of WMD (P </=.0005). CONCLUSIONS In this study IVH and ventriculomegaly were powerful predictors of WMD occurrence, whether small or large, unilateral or bilateral, localized or diffuse.