Clinical management and outcome of head and neck paragangliomas (HNPGLs): A single centre retrospective study.

CONTEXT: Head and neck paragangliomas (HNPGLs) are rare, usually benign, slow-growing tumours arising from neural crest-derived tissue. Definitive management pathways for HNPGLs have yet to be clearly defined. OBJECTIVE: To review our experience of the clinical features and management of these tumours and to analyse outcomes of different treatment modalities. METHODS: Demographic and clinical data were obtained from The Northern Ireland Electronic Care Record (NIECR) as well from a prospectively maintained HNPGL database between January 2011 through December 2023. RESULTS: There were 87 patients; 50 females: 37 males with a mean age of 52.3 ± 14.2 years old (range 17-91 years old). 58.6% (n = 51) of patients had carotid body tumours, 25.2% (n = 22) glomus vagal tumours, 6.8% (n = 6) tumours in the middle ear, 2.2% (n = 2) in the parapharyngeal space and 1.1% (n = 1) in the sphenoid sinus. 5.7% (n = 5) of patients had multifocal disease. The mean tumour size at presentation was 3.2 ± 1.4 cm (range 0.5-6.9 cm). Pathogenic SDHD mutations were identified in 41.3% (n = 36), SDHB in 12.6% (n = 11), SDHC in 2.2% (n = 2) and SDHA in 1.1% (n = 1) of the patients. Overall treatment modalities included surgery alone in 51.7% (n = 45) of patients, radiotherapy in 14.9% (n = 13), observation in 28.7% (n = 25), and somatostatin analogue therapy with octreotide in 4.5% (n = 4) of patients. Factors associated with a significantly higher risk of recurrence included age over 60 years (p = .04), tumour size exceeding 2 cm (p = .03), positive SDHx variants (p = .01), and vagal and jugular tumours (p = .04). CONCLUSION: The majority of our patients underwent initial surgical intervention and achieved disease stability. Our results suggest that carefully selected asymptomatic or medically unfit patients can be safely observed provided lifelong surveillance is maintained. We advocate for the establishment of a UK and Ireland national HNPGL registry, to delineate optimal management strategies for these rare tumours and improve long term outcomes.

Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations.

CONTEXT: Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors. OBJECTIVE: To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs. DESIGN: We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored. RESULTS: Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs. CONCLUSION: ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors.

Detection of vertebral fracture in an acute hospital setting: an intervention to reduce future fracture risk through fracture liaison service intervention?

We introduced a standardised reporting system in the radiology department to highlight vertebral fractures and to signpost fracture prevention services. Our quality improvement project achieved improved fracture reporting, access to the FLS service, bone density assessment and anti-fracture treatment. PURPOSE: Identification of vertebral fragility fractures (VF) provides an opportunity to identify individuals at high risk who might benefit from secondary fracture prevention. We sought to standardise VF reporting and to signpost fracture prevention services. Our aim was to improve rates of VF detection and access to our fracture liaison service (FLS). METHODS: We introduced a standardised reporting tool within the radiology department to flag VFs with signposting for referral for bone densitometry (DXA) and osteoporosis assessment in line with Royal Osteoporosis Society guidelines. We monitored uptake of VF reporting during a quality improvement phase and case identification within the FLS service. RESULTS: Recruitment of individuals with VF to the FLS service increased from a baseline of 63 cases in 2017 (6%) to 95 (8%) in 2018 and 157 (8%) in 2019 and to 102 (12%) in the first 6 months of 2020 (p = 0.001). One hundred fifty-three patients with VFs were identified during the QI period (56 males; 97 females). Use of the terminology 'fracture' increased to 100% (mean age 70 years; SD 13) in computed tomography (n = 110), plain X-ray (n = 37) or magnetic resonance imaging (n = 6) reports within the cohort. Signposting to DXA and osteoporosis assessment was included in all reports (100%). DXA was arranged for 103/153; 12 failed to attend. Diagnostic categories were osteoporosis (31%), osteopenia (36%) or normal bone density (33%). A new prescription for bone protection therapy was issued in 63/153. Twelve of the series died during follow-up. CONCLUSIONS: Standardisation of radiology reporting systems facilitates reporting of prevalent vertebral fractures and supports secondary fracture prevention strategies.

A service evaluation of e-triage in the osteoporosis outpatient clinic-an effective tool to improve patient access?

We introduced an electronic triage system into our osteoporosis service to actively manage referral demand in a busy outpatient service. Our study demonstrated the effectiveness of e-triage in supporting alternative management pathways, through use of virtual advice and direct to investigation services, to improve patient access. PURPOSE: Osteoporosis referrals are increasing with awareness of the potential for prevention of fragility fracture and with complex decision making around management with long-term bisphosphonate therapy. We examined whether active triage of referrals might improve referral management processes and patient access to osteoporosis services. METHODS: We implemented electronic triage (e-triage) of referrals to our osteoporosis service using the Northern Ireland electronic health care record. This included the option of 'advice only', direct to investigation with DXA or face-to-face appointments at the consultant-led complex osteoporosis service. We anticipated that there was scope to manage patient flow direct to investigation, or to provide referring clinicians with clinical advice without the need for a face-to-face assessment, at the consultant-led specialist service. RESULTS: We reviewed e-triage outcomes of 809 referrals (692 F; 117 M) to osteoporosis specialist services (mean age 65 ± 16.5 years) over a 12-month period. There was a high degree of agreement for the triage category between the referring clinician and specialist services (741/809). 73.3% attended a face-to-face appointment at the consultant-led clinic, while active triage enabled direct to investigation (18.4%) or discharge (8.3%) in the remainder. The mean time between receipt of an electronic referral and e-triage was 3 days over the 12-month period as compared with 2.1 days (median 1.1 days) when annual leave periods were excluded. CONCLUSION: E-triage supports effective referral management in a busy osteoporosis service. Efficiency is limited by reliance on a sole clinician and 5 day working at present. There is scope to further improve systems access through multidisciplinary team working, virtual clinics and future information technology developments.

Diabetes distress, illness perceptions and glycaemic control in adults with type 2 diabetes.

The emotional distress associated with adjusting to and living with diabetes has been termed diabetes distress. Diabetes distress is associated with glycaemic control but interventions to reduce diabetes distress have failed to consistently improve diabetes control. Various illness perceptions have previously been linked with both diabetes distress and glycaemic control but interrelationships between these features have not been previously investigated. We hypothesised that illness perceptions mediate the relationship between diabetes distress and glycaemia. Participants with type 2 diabetes attending diabetes outpatient clinics (n = 84) provided demographic and clinical information and completed the Diabetes Distress Scale-17 and the Brief Illness Perceptions Questionnaire. Using regression analysis we demonstrated that the illness perceptions of personal control, regimen-related distress, socioeconomic status and insulin use were significant contributors in the final model predicting HbA1c. Higher levels of personal control were associated with better glycaemic control. Conversely, regimen-related distress was associated with hyperglycaemia. Mediation analyses showed that the relationship between regimen-related distress and HbA1c was mediated by personal control. Our work suggests that psychological interventions designed to reduce diabetes distress may be more efficacious in improving glycaemic control if they address an individual's perception of personal control.

Diabetes distress: understanding the hidden struggles of living with diabetes and exploring intervention strategies.

Diabetes distress is a rational emotional response to the threat of a life-changing illness. Distinct from depression, it is conceptually rooted in the demands of diabetes management and is a product of emotional adjustment. Diabetes distress has been found to be significantly associated with glycated haemoglobin (HbA1c) level and the likelihood of an individual adopting self-care behaviours. The lack of perceived support from family, friends and healthcare professionals significantly contributes to elevated diabetes distress, and this issue tends to be overlooked when designing interventions. Pioneering large-scale research, DAWN2, gives voices to the families of those with diabetes and reaffirms the need to consider psychosocial factors in routine diabetes care. Structured diabetes education programmes are the most widely used in helping individuals cope with diabetes, but they tend not to include the psychological or interpersonal aspects of diabetes management in their curricula. The need for health practitioners, irrespective of background, to demonstrate an understanding of diabetes distress and to actively engage in discussion with individuals struggling to cope with diabetes is emphasised.

Hypopituitarism as the presenting feature of bronchogenic carcinoma with metastases to the pituitary gland.

Tumours metastasizing to the pituitary gland are uncommon. Symptomatic patients with pituitary metastases can present with diabetes insipidus, headache, visual field defects and/or anterior pituitary hormonal dysfunction. Treatment options for pituitary metastases include, surgical resection, cranial or parasellar irradiation and/or chemotherapy, and hormonal replacement if indicated. The overall prognosis of pituitary metastases is poor. We present a case of hypopituitarism as the presenting feature of bronchogenic carcinoma with metastases to the pituitary gland.

The postoperative basal cortisol and CRH tests for prediction of long-term remission from Cushing's disease after transsphenoidal surgery.

CONTEXT: Selective adenomectomy via transsphenoidal surgery induces remission of Cushing's disease (CD) in most patients. Although an undetectable postoperative serum cortisol (<2 µg/dl) has been advocated as an index of remission, there is no consensus on predictors of recurrence. OBJECTIVE: We hypothesized that patients with subnormal cortisol (2-4.9 µg/dl) might achieve long-term remission and that postoperative responses to CRH might predict recurrence. DESIGN, SETTING, AND PARTICIPANTS: We prospectively studied CD patients with initial remission after adenomectomy or hemihypophysectomy (n = 14). Long-term recurrence (n = 39) or remission (n = 293) was assigned by laboratory results, glucocorticoid dependence, or patient survey at a mean of 10.6 yr after surgery. INTERVENTION AND MAIN OUTCOME MEASURES: Postoperatively, morning cortisol was measured on d 3-5, and cortisol and ACTH responses to ovine CRH were assessed around d 10. RESULTS: Follow-up duration was median 11 yr (range 1-22.8 yr). Fewer patients achieved a cortisol nadir below 2 µg/dl (87%) than below 5 µg/dl (98%), yet recurrence rates were similar (<2 µg/dl, 9.5%; <5 µg/dl, 10.4%; 2-4.9 µg/dl, 20%; not significant). CRH-stimulated cortisol (P < 0.002) and ACTH (P = 0.04) values were higher for the recurrence than the remission group. However, no basal or stimulated ACTH or serum or urine cortisol cutoff value predicted all who later recurred. CONCLUSIONS: A postoperative cortisol below 2 µg/dl predicts long-term remission after transsphenoidal surgery in CD. Remission in those with intermediate d 3-5 postoperative cortisol values (2-4.9 µg/dl) suggests that these patients do not require immediate reoperation. However, because no single cortisol cutoff value excludes all patients with recurrence, all require long-term clinical follow-up.

Insulinotropic actions of nateglinide in type 2 diabetic patients and effects on dipeptidyl peptidase-IV activity and glucose-dependent insulinotropic polypeptide degradation.

BACKGROUND: Nateglinide restores early-phase insulin secretion to feeding and reduces postprandial hyperglycaemia in type 2 diabetes. This study evaluated the effects of nateglinide on dipeptidyl peptidase-IV (DPP-IV) activity and glucose-dependent insulinotropic polypeptide (GIP) degradation. Research design and methods Blood samples were collected from type 2 diabetic subjects (n=10, fasting glucose 9.36+/-1.2 mmol/l) following administration of oral nateglinide (120 mg) 10 min prior to a 75 g oral glucose load in a randomised crossover design. RESULTS: Plasma glucose reached 18.2+/-1.7 and 16.7+/-1.7 mmol/l at 90 min in control and placebo groups (P<0.001). These effects were accompanied by prompt 32% inhibition of DPP-IV activity after 10 min (19.9+/-1.6 nmol/ml per min, P<0.05), reaching a minimum of 1.9+/-0.1 nmol/ml per min at 120 min (P<0.001) after nateglinide. Insulin and C-peptide levels increased significantly compared with placebo, to peak after 90 min at 637.6+/-163.9 pmol/l (P<0.05) and 11.8+/-1.4 mg/l (P<0.01) respectively. DPP-IV-mediated degradation of GIP was significantly less in patients receiving nateglinide compared with placebo. Inhibition of DPP-IV activity corresponded with a time- and concentration-dependent inhibitory effect of nateglinide on DPP-IV-mediated truncation of GIP(1-42) to GIP(3-42) in vitro. Comparison of in vitro inhibition of DPP-IV by nateglinide and vildagliptin revealed IC(50) values of 17.1 and 2.1 microM respectively. CONCLUSIONS: Although considerably less potent than specified DPP-IV inhibitors, the possibility that some of the beneficial actions of nateglinide are indirectly mediated through DPP-IV inhibition and increased bioavailability of GIP and other incretins merits consideration.

Decreased dipeptidyl peptidase-IV activity and glucagon-like peptide-1(7-36)amide degradation in type 2 diabetic subjects.

Dipeptidyl peptidase (DPP-IV) rapidly metabolizes hormones such as glucagon-like peptide-1(7-36)amide. This study evaluated circulating DPP-IV activity in type 2 diabetic patients in relation to GLP-1 degradation and metabolic control. Blood samples were collected from type 2 diabetic patients in three main categories: good glycaemic control (HbA(1c) <7%, upper limit of non-diabetic range), moderate glycaemic control (HbA(1c) 7-9%) and poor glycaemic control (HbA(1c) >9%). Age- and sex-matched non-diabetic subjects were used as controls. Circulating DPP-IV activity of healthy control subjects was 22.5+/-0.7 nmol/ml/min (n=70). In the combined groups of type 2 diabetic subjects, circulating DPP-IV activity was significantly decreased at 18.1+/-0.7 nmol/ml/min (p<0.001, n=54). DPP-IV activity was negatively correlated with both glucose (p<0.01) and HbA(1c) (p<0.01) in this population. Furthermore, DPP-IV activity was reduced 1.2-fold (p<0.01, n=25), 1.3-fold (p<0.001, n=19) and 1.3-fold (p<0.05, n=10) in good, moderate and poorly controlled diabetic groups, 18.7+/-1.0, 17.4+/-1.4 and 18.0+/-1.5 nmol/ml/min, respectively. Degradation of GLP-1 by in vitro incubation with pooled plasma samples from healthy and type 2 diabetic subjects revealed decreased degradation to the inactive metabolite, GLP-1(9-36), in the diabetic group. These data indicate decreased DPP-IV activity and GLP-1 degradation in type 2 diabetes. DPP-IV enzyme activity appears to be depressed in response to poor glycaemic control.

Long-term impaired quality of life in Cushing's syndrome despite initial improvement after surgical remission.

CONTEXT: Cushing's syndrome (CS) is associated with symptoms that may impair health-related quality of life (HRQL). METHODS: We used the short-form 36 survey to evaluate HRQL in 23 patients with Cushing's disease before and after transsphenoidal surgery (age, 42.7 +/- 12.0 yr; 19 women and four men) and in a cross-section of 343 CS patients (age, 48.2 +/- 14.1 yr; 265 women and 78 men) in remission for up to 25.8 yr after surgery (adrenal, 5%; ectopic, 6%). The z-scores were calculated for short-form 36 domains, and physical (PCS) and mental (MCS) summary scores were compared with those of age- and sex-matched controls (n = 6742). RESULTS: Active Cushing's disease was associated with low PCS and MCS scores (P < 0.05). Despite residual postoperative impairment, primarily of physical domains, all HRQL parameters improved after treatment with transsphenoidal surgery (3.2 +/- 1.5 yr; P < 0.05). In the cross-section in remission at follow-up, there was a small, but significant (P < 0.05), impairment of both PCS and MCS. A longitudinal postoperative analysis confirmed stable, but impaired, HRQL over time. Logistic regression demonstrated that previous pituitary radiation and current glucocorticoid use had little effect on HRQL outcomes. CONCLUSION: CS is associated with impaired HRQL, which partially resolves after treatment. At longer-term follow-up, however, there is residual impairment of HRQL. Determination of modifiable factors that contribute to impaired HRQL may help reduce the physical and psychosocial burden of this disease.

Fibroblast growth factor-23 is regulated by 1alpha,25-dihydroxyvitamin D.

UNLABELLED: Serum FGF-23 regulation was studied in patients with hypoparathyroidism or pseudohypoparathyroidism treated with calcitriol. Serum FGF-23 levels changed in parallel in response to changes in serum 1,25-D, suggesting that FGF-23 may be regulated by 1,25-D. In addition, the phosphaturic effect of FGF-23 may be diminished in the absence of PTH action on the kidney. INTRODUCTION: Fibroblast growth factor (FGF)-23 is a recently described hormone that has been shown to be involved in the regulation of phosphate and vitamin D metabolism. The physiologic role of FGF-23 in mineral metabolism and how serum FGF-23 levels are regulated have yet to be elucidated. Three patients with mineral metabolism defects that allowed for the investigation of the regulation of FGF-23 were studied. MATERIALS AND METHODS: Patient 1 had postsurgical hypoparathyroidism and Munchausen's syndrome and consumed a pharmacologic dose of calcitriol. Patient 2 had postsurgical hypoparathyroidism and fibrous dysplasia of bone. She was treated with increasing doses of calcitriol followed by synthetic PTH(1-34). Patient 3 had pseudohypoparathyroidism type 1B and tertiary hyperparathyroidism. She underwent parathyroidectomy, which was followed by the development of hungry bone syndrome and hypocalcemia, requiring treatment with calcitriol. Serum FGF-23 and serum and urine levels of mineral metabolites were measured in all three patients. RESULTS: Patient 1 had an acute and marked increase in serum FGF-23 (70 to 670 RU/ml; normal range, 18-108 RU/ml) within 24 h in response to high-dose calcitriol administration. Patient 2 showed stepwise increases in serum FGF-23 from 117 to 824 RU/ml in response to increasing serum levels of 1alpha,25-dihydroxyvitamin D (1,25-D). Finally, before parathyroidectomy, while hypercalcemic, euphosphatemic, with low levels of 1,25-D (10 pg/ml; normal range, 22-67 pg/ml), and with very high serum PTH (863.7 pg/ml; normal range, 6.0-40.0 pg/ml), patient 3 had high serum FGF-23 levels (217 RU/ml). After surgery, while hypocalcemic, euphosphatemic, and with high serum levels of serum 1,25-D (140 pg/ml), FGF-23 levels were higher than preoperative levels (305 RU/ml). It seemed that the phosphaturic effect of FGF-23 was diminished in the absence of PTH or a PTH effect. CONCLUSIONS: Serum FGF-23 may be regulated by serum 1,25-D, and its phosphaturic effect may be less in the absence of PTH.

The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment.

Pregnancy dramatically affects the hypothalamic-pituitary-adrenal axis leading to increased circulating cortisol and ACTH levels during gestation, reaching values in the range seen in Cushing's syndrome (CS). The cause(s) of increased ACTH may include placental synthesis and release of biologically active CRH and ACTH, pituitary desensitization to cortisol feedback, or enhanced pituitary responses to corticotropin-releasing factors. In this context, challenges in diagnosis and management of disorders of the hypothalamic-pituitary-adrenal axis in pregnancy are discussed. CS in pregnancy is uncommon and is associated with fetal morbidity and mortality. The diagnosis may be missed because of overlapping clinical and biochemical features in pregnancy. The proportion of patients with primary adrenal causes of CS is increased in pregnancy. CRH stimulation testing and inferior petrosal sinus sampling can identify patients with Cushing's disease. Surgery is a safe option for treatment in the second trimester; otherwise medical therapy may be used. Women with known adrenal insufficiency that is appropriately treated can expect to have uneventful pregnancies. Whereas a fetal/placental source of cortisol may mitigate crisis during gestation, unrecognized adrenal insufficiency may lead to maternal or fetal demise either during gestation or in the puerperium. Appropriate treatment and management of labor are reviewed.

Differential diagnosis and imaging in Cushing's syndrome.

Establishing the cause of Cushing's syndrome (CS) is one of the most challenging processes in clinical endocrinology. Biochemical testing, including measurement of plasma adrenocorticotropin (ACTH), high-dose dexamethasone suppression, and corticotropin-releasing hormone stimulation testing, is integral to the differential diagnosis. No existing test has sufficient diagnostic accuracy when used alone, however. The adjunctive use of focused imaging, including CT, MRI, and nuclear imaging modalities, often can provide a diagnosis. In patients with ACTH-dependent CS, bilateral inferior petrosal sinus sampling can facilitate a diagnosis in those with discrepant clinical features, biochemistry, or imaging. This article focuses on current biochemical and radiologic strategies for the differential diagnosis of CS.

Reduced prevalence of limited joint mobility in type 1 diabetes in a U.K. clinic population over a 20-year period.

OBJECTIVE: Limited joint mobility (LJM), one of the earliest clinically apparent long-term complications of type 1 diabetes, is a risk marker for subsequent microvascular complications. We hypothesize that the prevalence of LJM may have decreased during the past two decades due to improved standards of glycemic control. RESEARCH DESIGN AND METHODS: A single observer performed a survey in 204 consecutive patients with type 1 diabetes (106 men and 98 women, age 27 +/- 1 years, HbA(1c) 8.3 +/- 0.1%, duration of diabetes 14.5 +/- 0.8 years, insulin dose 63 +/- 2 units/day). We used the same examination method and criteria for assessment of LJM as used by us in an earlier study in 1981-1982. RESULTS: The prevalence of LJM has fallen from 43 to 23% between the 1980s and 2002 (P < 0.0001). The relative risk for LJM in 2002 compared with the 1981-1982 cohort was 0.53 (0.40 < RR < 0.72, P < 0.0001). The prevalence of LJM was increased with longer duration of diabetes (<10 years, 13%; 10-20 years, 19%; 20-29 years, 30%; >30 years, 65%; P < 0.001). The relative risk for those with a mean HbA(1c) <7% in 2002 was 0.3 (0.1 < RR < 1.2, P = 0.05) when compared with those with mean HbA(1c) >7%. CONCLUSIONS: The present study confirms the hypothesis that the prevalence of LJM is lower than 20 years ago and that improved standards of glycemic control and diabetes care may have contributed to this occurrence. Joint limitation in type 1 diabetes is strongly associated with duration of diabetes. The presence of LJM remains a common and important clinical marker for subsequent microvascular disease and can be a useful clinical tool for identification of patients at increased risk.

Cushing's syndrome during pregnancy: personal experience and review of the literature.

Cushing's syndrome (CS) occurs rarely during pregnancy. We investigated and treated four patients with pituitary-dependent Cushing's syndrome during pregnancy over a 15-yr period at the National Institutes of Health. Except for preservation of menses before conception, our patients presented with typical clinical features, increased urinary free cortisol, and loss of diurnal variation of cortisol. The diagnosis was facilitated, without complications, by the use of CRH testing and inferior petrosal sinus sampling in three women. Transsphenoidal pituitary surgery achieved remission in three women, but there were two fetal/neonatal deaths. This experience and review of 136 previous reports suggest that: 1) urinary free cortisol in CS patients overlaps the normal pregnant range; 2) ACTH levels are not suppressed in adrenal causes of CS, which may be identified by the 8-mg dexamethasone test; 3) inferior petrosal sinus sampling and transsphenoidal pituitary surgery, the optimal diagnostic test and treatment for nonpregnant patients with pituitary-dependent Cushing's syndrome, can safely facilitate the management of pregnant patients; and 4) surgery may achieve remission during pregnancy, but the prognosis for the fetus remains guarded. It is likely that earlier recognition and treatment would improve outcome. There is a need for development of criteria for interpretation of diagnostic tests and increased consideration of CS in pregnancy.