Thyroid disease symptoms during early pregnancy do not identify women with thyroid hypofunction that should be treated.

OBJECTIVE: To evaluate whether women during early pregnancy with "hypothyroidism" symptoms are at risk of biochemically defined hypothyroidism. The 2017 Guidelines of the American Thyroid Association (ATA) recommend case-finding on the basis of symptoms to identify these women during pregnancy, while evidence is lacking. DESIGN: Construct validation of a thyroid hypofunction symptom checklist during the first trimester of pregnancy comparing high scores with biochemically defined hypothyroidism. PATIENTS: A total of 2198 healthy pregnant women from an iodine-sufficient area in 2013-2014. MEASUREMENTS: Completion of a draft questionnaire with "classical" symptoms of hypothyroidism at 12 weeks of gestation. The 2.5th and 97.5th percentiles of TSH and fT4 during pregnancy in TPO-Ab-negative (<35 kU/L) women were used to define euthyroid women and those with overt (clinical) and subclinical hypothyroidism. The prevalence of overt (subclinical) hypothyroidism was compared between women with high symptom scores and those with low symptom scores. RESULTS: According to fT4 and TSH cut-offs (0.23-4.0 mIU/L and 11.5-18.0 pmol/L, respectively), there were 15 women with "to treat hypofunction" (overt hypothyroidism or TSH >10 mIU/L) and 68 women with subclinical hypothyroidism. Questionnaire construct validation revealed a 12-item hypothyroid checklist with normally distributed scores. The cut-off indicating high scores of OH was set at 1 SD > mean. Women with high symptom scores did not present more often with biochemically defined thyroid hypofunction. CONCLUSION: This study does not support the ATA recommendation that pregnant women who require levothyroxine therapy can be identified by case-based screening of women with symptoms of thyroid disease.

Thyroid disease in pregnant women with systemic lupus erythematosus: increased preterm delivery.

Thyroid disease is common in pregnancy and is associated with miscarriage, preterm delivery and postpartum thyroiditis (PPT). Systemic lupus erythematosus (SLE) is associated with miscarriage and preterm delivery. The hypotheses of the study are (1) pregnant women with SLE will have a high prevalence of undiagnosed hypothyroidism and a high prevalence of PPT, and (2) women with SLE and thyroid disease will have an increased incidence of adverse pregnancy outcomes as compared with pregnant women with SLE who do not have thyroid disease. This was a retrospective study of the Hopkins Lupus Cohort. All women had thyroid-stimulating hormone and thyroid antibodies assayed on frozen sera. In total, 63 pregnant women who met the ACR classification for SLE were evaluated. Outcome measures were the prevalence of thyroid disease during pregnancy and postpartum, and pregnancy outcomes. Some 13% of the women were on thyroid hormone prior to becoming pregnant, 11% were diagnosed with hypothyroidism during pregnancy, and 14% developed PPT. The prevalence of preterm delivery was 67% in women with thyroid disease and 18% in women who were thyroid disease free (p = 0.002). The presence of thyroid antibodies was not correlated with preterm delivery. Pregnant women with SLE have an increased prevalence of thyroid disease. Women with SLE and thyroid disease have an increased prevalence of preterm delivery.

Leukocyte scanning with 111In is superior to magnetic resonance imaging in diagnosis of clinically unsuspected osteomyelitis in diabetic foot ulcers.

OBJECTIVE: To compare the accuracies of MRI and leukocyte scanning in diagnosing clinically unsuspected osteomyelitis in diabetic foot ulcers. RESEARCH DESIGN AND METHODS: A prospective study of 16 diabetic foot ulcers in 12 patients, including both ambulatory and hospitalized patients, was performed at a university medical center. Pedal images were obtained by leukocyte scanning with [111In]oxyquinoline and MRI. Definitive diagnosis of osteomyelitis then was determined by bone biopsy for culture and histology. RESULTS: Biopsy-proven osteomyelitis was present in 7 (44%) of the 16 foot ulcers. The diagnosis was suspected clinically in 0%. Leukocyte scanning was 100% sensitive, whereas MRI was only 29% sensitive in diagnosing osteomyelitis in diabetic foot ulcers. Specificities were 67 and 78%, respectively. The positive and negative predictive values (70 and 100%, respectively) for the leukocyte scan also were greater than those of MRI (50 and 58%, respectively). CONCLUSIONS: Leukocyte scanning is superior to MRI in detecting clinically unsuspected osteomyelitis in diabetic foot ulcers.

Long-term prospective study of postpartum thyroid dysfunction in women with insulin dependent diabetes mellitus.

Postpartum thyroid dysfunction (PPTD) is a common autoimmune disorder. Type I diabetes mellitus (IDDM) is an autoimmune disease with a high incidence of concomitant autoimmune thyroid failure. We hypothesized that women with IDDM would have an increased incidence of PPTD. Women with IDDM in New York City, were followed prospectively during the second and third trimester of pregnancy and at 6 weeks, 3 months, 6 months, 9 months, and 1 yr postpartum. A long-term follow-up was performed at 31 months postpartum. Forty-one women with IDDM were recruited at their initial prenatal visit. Two women (4.8%) had thyroid function test abnormalities observed at screening, three (7.3%) had a spontaneous miscarriage, and eight (19.5%) women were noncompliant with follow-up. Twenty-eight women (68.2%) completed the study. Thyroid function tests and thyroid autoantibody determinations were obtained at all visits. PPTD was defined as a TSH greater than 5.0 or less than 0.2 mU/L in the postpartum period with documented normal thyroid function tests during pregnancy. The incidence of PPTD in women with IDDM was 25%. This is a 3-fold increase compared to a similar study by our group in a nondiabetic population. Forty-three percent of the women (3/7) who developed PPTD required treatment in the immediate postpartum period and at long-term follow-up. The remainder of the women with PPTD, as well as all women who did not develop PPTD were euthyroid at 31 months postpartum. Women with IDDM are at high risk for PPTD. We recommend that all women with IDDM be screened for thyroid hormonal abnormalities during pregnancy and at 3 months postpartum for postpartum thyroid dysfunction. Long-term follow-up did not reveal an increased incidence of hypothyroidism in women who did not require treatment in the first postpartum year.

A prospective study of lymphocyte-initiated immunosuppression in normal pregnancy: evidence of a T-cell etiology for postpartum thyroid dysfunction.

Immune function in normal pregnancy and the postpartum period remains poorly defined. We hypothesized that a comparative study between pregnant women with normal and abnormal immune function would further our understanding of the immune mechanisms of pregnancy. We chose to study a cohort of pregnant women at risk for the development of postpartum thyroid dysfunction (PPTD) as well as a group of normal controls. We chose PPTD as the model for abnormal immune function because of the relative ease of monitoring disease development and the relatively high prevalence for PPTD reported in earlier studies. Five hundred and fifty-two women were screened for the presence of thyroid autoantibodies in the first trimester of pregnancy. Thirty-three thyroid autoantibody-positive women and 28 thyroid autoantibody-negative women were followed prospectively throughout pregnancy and 6 months into the postpartum period. Lymphocyte subset analyses, thyroid function tests, and thyroid autoantibodies (antihuman thyroglobulin and antithyroid peroxidase) were performed at defined intervals. All patients were HLA serotyped. Normal pregnancy was principally characterized by decreased CD4+ T-cells and increasing CD8+ T-cells, causing a significant fall in the CD4+/CD8+ ratio in late pregnancy and into the postpartum period. Women who developed PPTD had 1) a higher CD4+/CD8+ ratio (P = 0.04), 2) activation of T-cells in the postpartum period (P = 0.02), and 3) significantly higher thyroid autoantibody titers (antihuman thyroglobulin, P = 0.02; antithyroid peroxidase, P = 0.0018). We found an overall incidence for PPTD of 8.8%. These data demonstrated that women who were thyroid autoantibody positive in the first trimester of pregnancy had a one in three chance of developing PPTD. We observed a significant fall in the T-cell helper/suppressor ratio in normal pregnant women, which was associated with distinct T-cell subset changes. This pregnancy-initiated T-cell regulation reflected an overall suppression of immune function. The development of PPTD was a frequent postpartum event in our population and was associated with a triad of immune markers: a reduction in the normal immune suppression of pregnancy (as indicated by higher T-cell helper/suppressor ratios), enhanced postpartum T-cell activation, and elevated thyroid autoantibodies. The reduction in the degree of immune suppression was, therefore, a major factor in the development of PPTD. Our results define immunological changes that occur in normal pregnancy and distinct immunological abnormalities necessary for the development of PPTD.

Recognizing, understanding, and treating postpartum thyroiditis.

Postpartum thyroiditis is the most common endocrinologic disorder, with an incidence that varies geographically from 5% to 10%. It has important clinical sequelae including symptoms of hyperthyroidism, hypothyroidism, and depression. Long-term follow-up of women who experience postpartum thyroiditis reveals a high recurrence rate in subsequent pregnancies. Postpartum thyroiditis is an autoimmune disorder, and thyroid antibody-positive women in the first trimester have a 33% to 50% chance of developing thyroiditis in the postpartum period. Whether or not to screen for postpartum thyroiditis remains controversial.

Post-miscarriage thyroid dysfunction.

BACKGROUND: Thyroid dysfunction is a common postpartum event affecting as many as 16.7% of women. The purpose of this paper was to report the first known case of post-miscarriage thyroid dysfunction. CASE: A 32-year-old woman with a 9-year history of infertility underwent in vitro fertilization. After two spontaneous miscarriages, she delivered a full-term healthy child. Spontaneous menses did not return following delivery, and hormonal evaluation revealed severe postpartum thyroid disease associated with hyperprolactinemia. Retrospective analysis of frozen sera revealed thyroid dysfunction and hyperprolactinemia after the first miscarriage, even though the gestation lasted only 47 days. CONCLUSION: The present case of thyroid dysfunction following a first-trimester miscarriage raises issues concerning the immunology of pregnancy and thyroid dysfunction after pregnancy. The incidence of post-miscarriage thyroid dysfunction and severe postpartum thyroid disease resulting in amenorrhea requires further study.

Thyroid antibodies and fetal loss: an evolving story.

This article reviews the literature on thyroid antibodies and miscarriage. In 1990, in a study designed to determine the incidence and etiology of postpartum thyroiditis, a serendipitous finding emerged revealing an association between thyroid antibodies and spontaneous miscarriage. Subsequently, four other studies, performed on three different continents, have confirmed the correlation. Six studies have evaluated the relationship between thyroid antibodies and recurrent abortion, defined as three or more spontaneous miscarriages. The majority of the studies (67%) reported a statistically significant increase in the incidence of thyroid antibodies in the recurrent abortion group as compared to controls. Four intervention trials have evaluated the impact of immunosuppressive therapy in women with thyroid antibodies. Although all of the trials revealed a decrease in the incidence of recurrent abortion, each study was limited by methodological concerns. A recently developed murine model of pregnancy has also demonstrated increased fetal loss in female mice immunized with thyroglobulin when mated with allogeneic males. The implications of these data generated over the last decade are discussed.

A multifaceted program to encourage medical students' research.

Clinician-scientists are important members of a research community that has more opportunities than ever before to solve problems important to patients. Nevertheless, the number of physicians applying for and receiving grants from the National Institutes of Health (NIH) has dropped. Introducing medical students to research and relevant support mechanisms early in their education may help to reverse this trend. In 1995, the Mount Sinai School of Medicine created its Office of Student Research Opportunities (OSRO) to stimulate students to engage in research. It also appointed a new dean to direct the OSRO; the person who filled this new position was a senior faculty member involved in patient-oriented research. The OSRO advises students, identifies faculty who want to mentor students, sponsors the Distinction in Research program, organizes an annual research day, helps fund summer and full-time research, and has created an endowment to support student travel to national meetings. Between 1997 and 2000 the number of students who participated in the research day increased from 18 to 74, and the number of publications by the graduating classes increased from 34 to 58 between 1997 and 1999. Participants have presented both basic and clinical projects. The authors' experience has shown that medical students can be motivated to carry out research with appropriate encouragement from the administration and the faculty, something that may help to reverse a troubling national trend. Based upon these early successes, Mount Sinai is developing a novel five-year program to provide medical students with research training.

Interleukin-6 levels are not increased in women with postpartum thyroid dysfunction.

Postpartum thyroid dysfunction (PPTD) is an autoimmune-mediated thyroid destructive process. Human interleukin-6 (IL-6) is a cytokine found to be increased in subacute thyroiditis, amiodarone-induced thyrotoxicosis, Graves' disease, and other thyroid destructive processes. We report serum IL-6 levels in PPTD in two independent studies. New York Study: In a previous prospective study we demonstrated that PPTD occurred in 25% (7/28) of women with type 1 diabetes mellitus. IL-6 determinations were made on the frozen serum samples of these 28 women during each trimester of their pregnancy and at 1.5, 3, 6, 9, and 12 months postpartum. IL-6 levels were found to be similar in women with PPTD compared with women without PPTD (mean 3.06+/-2.25 vs. 2.51+/-2.21 pg/mL; p = 0.15). No difference in IL-6 levels was found between the pre- and the postpartum periods (mean 2.67+/-1.82 vs. 3.04+/-2.44 pg/mL; p = 0.30) in all 28 women. Cardiff Study: Serum IL-6 levels were measured on frozen serum samples of 30 women with PPTD. IL-6 levels were below the detection limit (25 fmol/L or 0.65 pg/mL) in 94 (67%) of these samples. No significant difference in the mean serum IL-6 levels were found between any time points in the study. There was no correlation between serum IL-6 levels, thyroid peroxidase (TPO)- antibodies and serum thyrotropin (TSH) levels at any time point. IL-6 levels during pregnancy or postpartum were not found to be significantly different in women with PPTD compared with women without PPTD.

Perioperative glucose control: does it really matter?

Perioperative management of the patient with diabetes presents unique challenges. The benefit of glycemic control must be balanced against the danger of hypoglycemia. Through a clear understanding of the hormonal and metabolic alterations that accompany surgery, as well as careful glucose monitoring, the diabetic can be safely and effectively managed during the perioperative period.

Medical education grand rounds.

The primary goal of Medical Education Grand Rounds is to enhance the overall educational mission of the Mount Sinai School of Medicine. This editorial describes the first four years of this unique and innovative educational program, and serves as a prelude to a new feature of The Journal.

Mortality in hospitalized patients with hypoglycemia and severe hyperglycemia.

BACKGROUND: We designed a study to determine the incidence, cause, and implications of hypoglycemia (< or = 2.7 mmol/L, 49 mg/dL) and severe hyperglycemia (> or = 22.2 mmol/L, 400 mg/dL) in in-patients at an urban tertiary medical center. METHODS: A daily computer search of the Laboratory Information System identified all hospitalized patients with hypoglycemia and severe hyperglycemia during a 49-day period. Chart review was used to assess demographic information, risk factors, and epidemiologic variables. The eventual outcome of the hospitalization was obtained by follow-up. RESULTS: The incidence of hypoglycemia was 1.5%, and of hyperglycemia, 1.9%. Seventy-six percent of the hypoglycemic patients and 16% of the hyperglycemic patients had no prior history of diabetes. The mortality rate for hypoglycemic patients was 22.2%; for hyperglycemic patients it was 11.1%. For all other hospitalized patients it was 2.3% (p < 0.0001). Mortality rates for the black and Hispanic patients who were hypoglycemic (30% and 46%) were significantly higher than for white patients (6%, p < 0.01). CONCLUSIONS: Hypoglycemia and severe hyperglycemia are not uncommon in hospitalized patients and serve as metabolic markers for patients at increased risk for inhospital mortality. Early identification of at-risk patients and the impact of aggressive treatment of their underlying disease processes should be evaluated in future studies.

An integrated program for evidence-based medicine in medical school.

To provide optimal care for their patients, clinicians must be able to locate and interpret the most current literature. Teaching the necessary skills to medical students is essential, if we wish to train clinicians to be able to keep up with the expansion of biomedical knowledge for their entire working lives. In this paper, we describe our school's four-year curriculum in evidence-based medicine and the performance of three senior classes on the summative evaluation exercise devised to measure the program's success.

The thyroid during pregnancy: a physiological and pathological stress test.

Pregnancy and the postpartum are times of marked and rapid change in the thyroid gland. Normal physiological changes include enhanced thyroid hormone production, modulation of thyroid hormone metabolism by placental deiodinases, and decreasing titers of thyroid antibodies in thyroid antibody positive women. Hyperemesis gravidarum is associated with suppressed thyroid stimulating hormone levels and free T4 elevations. Graves' disease typically becomes quiescent during pregnancy, followed by a postpartum flare. Women with pre-existing hypothyroidism frequently require an increase in their levothryoxine requirement in the 1(st) trimester, and subclinical hypothyroidism early in pregnancy is linked to both miscarriage and impaired neurological development in the unborn child. Postpartum thyroiditis occurs in 7.2% of women, and euthyroid women who are thyroid antibody positive in the 1(st) trimester of pregnancy have a doubling of the miscarriage rate.